Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.

Patents

  1. Advanced Patent Search
Publication numberUS20060258638 A1
Publication typeApplication
Application numberUS 11/492,593
Publication dateNov 16, 2006
Filing dateJul 25, 2006
Priority dateAug 7, 1998
Also published asCA2338944A1, CN1311779A, DE69927827D1, DE69927827T2, EP1102752A1, EP1102752B1, US7304055, US7304056, US20060264417, WO2000007995A1
Publication number11492593, 492593, US 2006/0258638 A1, US 2006/258638 A1, US 20060258638 A1, US 20060258638A1, US 2006258638 A1, US 2006258638A1, US-A1-20060258638, US-A1-2006258638, US2006/0258638A1, US2006/258638A1, US20060258638 A1, US20060258638A1, US2006258638 A1, US2006258638A1
InventorsRichard Olson, Thomas Maduskuie, Lorin Thompson
Original AssigneeBristol-Myers Squibb Pharma Company
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Succinoylamino lactams as inhibitors of A-beta protein production
US 20060258638 A1
Abstract
This invention relates to novel lactams having drug and bio-affecting properties, their pharmaceutical compositions and methods of use. These novel compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Aβ-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein. More particularly, the present invention relates to the treatment of neurological disorders related to β-amyloid production such as Alzheimer's disease and Down's Syndrome.
Images(114)
Previous page
Next page
Claims(41)
1. (canceled)
2. A compound of Formula (I)
or a pharmaceutically acceptable salt form thereof,
wherein
A is O;
Q is —NR1R2;
R1, at each occurrence, is independently selected from:
H;
C1-C6 alkyl substituted with 0-3 R1a;
C2-C6 alkenyl substituted with 0-3 R1a;
R1a, at each occurrence, is independently selected from H, OR14, F, ═O, NR15R16, CF3;
C3-C6 cycloalkyl substituted with 0-3 R1b;
phenyl substituted with 0-3 R1b; and
5 to 6 membered heterocycle substituted with 0-3 R1b;
R1b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R2 is independently selected from H, NH2, OH, C1-C6 alkyl, C1-C6 alkoxy, phenoxy, and benzyloxy;
R3 is (CR7R7a)n—R4,
—(CR7R7a)n—S—(CR7R7a)m—R4,
—(CR7R7a)n—O—(CR7R7a)m—R4,
—(CR7R7a)n—N(R7b)—(CR7R7a)m—R4,
—(CR7R7a)n—S(═O)—(CR7R7a)m—R4,
—(CR7R7a)n—S(═O)2—(CR7R7a)m—R4,
—(CR7R7a)n—C(═O)—(CR7R7a)m—R4,
—(CR7R7a)n—NHC(═O)—(CR7R7a)m—R4,
—(CR7R7a)n—C(═O)NH—(CR7R7a)m—R4,
—(CR7R7a)n—NHS(═O)2—(CR7R7a)m—R4, or
—(CR7R7a)n—S(═O)2NH—(CR7R7a)m—R4;
n is 0, 1, 2, or 3;
n is 0, 1, 2, or 3;
R3a is H, OH, OH, C1-C4 alkyl, C1-C4 alkoxy, or C2-C4 alkenyloxy;
R4 is H, OH, OR14a,
C1-C6 alkyl substituted with 0-3 R4a,
C2-C6 alkenyl substituted with 0-3 R4a,
C2-C6 alkynyl substituted with 0-3 R4a,
C1-C10 carbocycle substituted with 0-3 R4b,
aryl substituted with 0-3 R4b, or
5 to 10 membered heterocycle substituted with 0-3 R4b;
R4a, at each occurrence, is independently selected from is H, F, Cl, Br, I, CF3,
C1-C10 carbocycle substituted with 0-3 R4b,
aryl substituted with 0-3 R4b, or
5 to 10 membered heterocycle substituted with 0-3 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R5 is H, OR14;
C1-C6 alkyl substituted with 0-3 R5b;
C1-C6 alkoxy substituted with 0-3 R5b;
C2-C6 alkenyl substituted with 0-3 R5b;
C2-C6 alkynyl substituted with 0-3 R5b;
C3-C10 carbocycle substituted with 0-3 R5c;
aryl substituted with 0-3 R5c; or
5 to 10 membered heterocycle substituted with 0-3R5c;
R5a is H, OH, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, or C2-C4 alkenyloxy;
R5b, at each occurrence, is independently selected from:
H, C1-C6 alkyl, CF3, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16;
C3-C10 carbocycle substituted with 0-3 R5c;
aryl substituted with 0-3 R5c; or
5 to 10 membered heterocycle substituted with 0-3 R5c;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R6 is H;
C1-C6 alkyl substituted with 0-3 R6a;
C3-C6 carbocycle substituted with 0-3 R6b; or
aryl substituted with 0-3R6b;
R6a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, phenyl or CF3;
R6b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R7, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, and C1-C4 alkyl;
R7a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, aryl and C1-C4 alkyl;
R7b is independently selected from H and C1-C4 alkyl;
W is —(CR8R8a)p—;
p is 0, 1, 2, 3, or 4;
R8 and R8a, at each occurrence, are independently selected from H, F, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and C3-C8 cycloalkyl;
X is a bond;
aryl substituted with 0-3 RXb;
C3-C10 carbocycle substituted with 0-3 RXb; or
5 to 10 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
Y is a bond or —(CR9R9a)t—V—(CR9R9a)u—;
t is 0, 1, 2, or 3;
u is 0, 1, 2, or 3;
R9 and R9a, at each occurrence, are independently selected from H, F, C1-C6 alkyl or C3-C8 cycloalkyl;
V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —N(R19)—, —C(═O)NR19b, —NR19bC(═O)—, —NR19bS(═O)2—, —S(═O)2NR19b, —NR19bS(═O)—, —S(═O)NR19b—, —C(═O)O—, or —OC(═O)—;
Z is C1-C3 alkyl substituted with 1-2 R12;
aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle substituted with 0-3 R12b;
R12 is aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
B is
R11, at each occurrence, is independently selected from
C1-C4 alkoxy, Cl, F, Br, I, ═O, CN, NO2, NR18R19, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, CF3;
C1-C6 alkyl substituted with 0-1 R11a;
aryl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; or
5 to 10 membered heterocycle substituted with 0-3 R11b;
alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle or a benzo fused radical;
R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R14 is H, phenyl, benzyl, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl);
R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl);
R17 is H, aryl, (aryl)CH2—, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
R18, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl); and
R19, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl); and
R19b is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or phenethyl.
3. A compound of claim 2 of Formula (Ia)
or a pharmaceutically acceptable salt thereof, wherein:
R3 is (CR7R7a)n—R4,
—(CR7R7a)n—S—(CR7R7a)m—R4,
—(CR7R7a)n—O—(CR7R7a)m—R4, or
—(CR7R7a)n—N(R7b)—(CR7R7a)m—R4;
n is 0, 1, or 2;
m is 0, 1, or 2;
R3a is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, or butoxy;
R4 is H, OH, OR14a,
C1-C4 alkyl substituted with 0-2 R4a,
C2-C4 alkenyl substituted with 0-2 R4a,
C2-C4 alkynyl substituted with 0-2 R4a,
C3-C6 cycloalkyl substituted with 0-3 R4b,
aryl substituted with 0-3 R4b, or
5 to 10 membered heterocycle substituted with 0-3 R4b;
R4a, at each occurrence, is independently selected from is H, F, Cl, Br, I CF3,
C3-C10 carbocycle substituted with 0-3 R4b,
aryl substituted with 0-3 R4b, or
5 to 10 membered heterocycle substituted with 0-3 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R5 is H, OR14;
C1-C6 alkyl substituted with 0-3 R5b;
C2-C6 alkenyl substituted with 0-3 R5b;
C2-C6 alkynyl substituted with 0-3 R5b;
C3-C10 carbocycle substituted with 0-3 R5c;
aryl substituted with 0-3 R5c; or
5 to 10 membered heterocycle substituted with 0-3R5c;
R5a is H, OH, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, or C2-C4 alkenyloxy;
R5b, at each occurrence, is independently selected from:
H, C1-C6 alkyl, CF3, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16;
C3-C10 carbocycle substituted with 0-3 R5c;
aryl substituted with 0-3 R5c; or
5 to 10 membered heterocycle substituted with 0-3 R5c;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R6 is H, methyl, or ethyl;
R7, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, and C1-C4 alkyl;
R7a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, phenyl and C1-C4 alkyl;
R7b is independently selected from H, methyl, ethyl, propyl, and butyl;
W is —(CR8R8a)p—;
p is 0, 1, or 2;
R8 and R8a, at each occurrence, are independently selected from H, F, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl and C3-C6 cycloalkyl;
X is a bond;
aryl substituted with 0-3 RXb;
C3-C10 carbocycle substituted with 0-2 RXb; or
5 to 10 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
Y is a bond or —(CR9R9a)t—V—(CR9R9a)u—;
t is 0, 1, or 2;
u is 0, 1, or 2;
R9 and R9a, at each occurrence, are independently selected from H, F, C1-C4 alkyl or C3-C6 cycloalkyl;
V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —N(R19)—, —C(═O)NR19b—, NR19bC(═O)—, —NR19bS(═O)2—, —S(═O)2NR19b—, —NR19bS(═O)—, or —S(═O)NR19b—;
Z is C1-C3 alkyl substituted with 1-2 R12;
aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle substituted with 0-3 R12b;
R12 is aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
B is
R11, at each occurrence, is independently selected from
C1-C4 alkoxy, Cl, F, ═O, NR18R19, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, CF3;
C1-C6 alkyl substituted with 0-1 R11a;
aryl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; or
5 to 10 membered heterocycle substituted with 0-3 R11b;
alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle or a benzo fused radical;
R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R14 is H, phenyl, benzyl, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl);
R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl);
R17 is H, aryl, (aryl)CH2—, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
R18, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl); and
R19, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl); and
R19b is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or phenethyl.
4. A compound of claim 3 or a pharmaceutically acceptable salt form thereof, wherein:
R3 is —(CR7R7a)n—R4,
—(CR7R7a)n—S—(CR7R7a)m—R4,
—(CR7R7a)n—O—(CR7R7a)m—R4, or
—(CR7R7a)n—N(R7b)-(CR7R7a)m—R4;
n is 0 or 1;
m is 0 or 1;
R3a is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, or butoxy;
R4 is H, OH,
C1-C4 alkyl substituted with 0-2 R4a,
C2-C4 alkenyl substituted with 0-2 R4a,
C2-C4 alkynyl substituted with 0-1 R4a,
C3-C6 cycloalkyl substituted with 0-3 R4b,
aryl substituted with 0-3 R4b, or
5 to 10 membered heterocycle substituted with 0-3 R4b;
R4a, at each occurrence, is independently selected from is H, F, Cl, CF3,
C3-C6 cycloalkyl substituted with 0-3 R4b,
phenyl substituted with 0-3 R4b, or
5 to 6 membered heterocycle substituted with 0-3 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R5 is H, OR14;
C1-C4 alkyl substituted with 0-3 R5b;
C2-C4 alkenyl substituted with 0-2 R5b; or
C2-C4 alkynyl substituted with 0-2 R5b;
R5a is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, or allyl;
R5b, at each occurrence, is independently selected from:
H, methyl, ethyl, propyl, butyl, CF3, OR14, ═O;
C3-C6 cycloalkyl substituted with 0-2 R5c;
phenyl substituted with 0-3 R5c; or
5 to 6 membered heterocycle substituted with 0-2 R5c;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R6 is H;
R7, at each occurrence, is independently selected from H, F, CF3, methyl, and ethyl;
R7a, at each occurrence, is independently selected from H, F, CF3, methyl, and ethyl;
R7b is independently selected from H, methyl, and ethyl;
W is a bond, —CH2—, —CH(CH3)—, —CH2CH2— or —CH(CH3)CH2—;
X is a bond;
phenyl substituted with 0-2 RXb;
C3-C6 cycloalkyl substituted with 0-2 RXb; or
5 to 6 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
Y is a bond, —CH2—V—, —V—, or —V—CH2—;
V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(CH3)—, or —N(CH2CH3)—,
Z is C1-C2 alkyl substituted with 1-2 R12;
aryl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-3 R12b; or
5 to 10 membered heterocycle substituted with 0-3 R12b;
R12 is aryl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-3 R12b; or
5 to 10 membered heterocycle substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
B is
R11, at each occurrence, is independently selected from
C1-C4 alkoxy, Cl, F, ═O, NR18R19, C(═O)R17, C(═O)OR17, CF3;
C1-C4 alkyl substituted with 0-1 R11a;
phenyl substituted with 0-3 R1b;
C3-C6 carbocycle substituted with 0-3 R11b; or
5 to 6 membered heterocycle substituted with 0-3 R11b;
alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a benzo fused radical;
R11a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, F, ═O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R14 is H, phenyl, benzyl, C1-C4 alkyl, or C2-C4 alkoxyalkyl;
R15, at each occurrence, is independently selected from H, C1-C4 alkyl, benzyl, phenethyl, —C(═O)—(C1-C4 alkyl) and —S(═O)2—(C1-C4 alkyl);
R16, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, benzyl, phenethyl, —C(═O)—(C1-C4 alkyl) and —S(═O)2—(C1-C4 alkyl);
R17 is H, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl, (4-methylphenyl)methyl, (4-trifluorophenyl)methyl, methyl, ethyl, propyl, butyl, methoxymethyl, methyoxyethyl, ethoxymethyl, or ethoxyethyl;
R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
R19, at each occurrence, is independently selected from H, methyl, and ethyl.
5. A compound of claim 4 of Formula (Ib)
or a pharmaceutically acceptable salt thereof, wherein:
R3 is —CH3, —CH2CH3, —CH2CH2CH3, —CH2CH2CH2CH3, —CH2(CH3)2, —CH(CH3)CH2CH3, —CH2CH(CH3)2, —CH2C(CH3)3, —CF3, —CH2CF3, —CH2CH2CF3, —CH2CH2CH2CF3, —CH═CH2, —CH2CH═CH2, —CH2C(CH3)═CH2, —CH2CH═C(CH3)2, —CH2CH2CH═CH2, —CH2CH2C(CH3)═CH2, —CH2CH2CH═C(CH3)2, cis-CH2CH═CH(CH3), cis-CH2CH2CH═CH(CH3), trans-CH2CH═CH(CH3), trans-CH2CH2CH═CH(CH3); —C≡CH, —CH2C≡CH, —CH2C═C(CH3), cyclopropyl-CH2—, cyclobutyl-CH2—, cyclopentyl-CH2—, cyclohexyl-CH2—, cyclopropyl-CH2CH2—, cyclobutyl-CH2CH2-cyclopentyl-CH2CH2—, cyclohexyl-CH2CH2—, phenyl-CH2—, (2-F-phenyl)CH2—, (3-F-phenyl)CH2—, (4-F-phenyl)CH2—, (2-Cl-phenyl)CH2—, (3-Cl-phenyl)CH2—, (4-Cl-phenyl)CH2—, (2,3-diF-phenyl)CH2—, (2,4-diF-phenyl)CH2—, (2,5-diF-phenyl)CH2—, (2,6-diF-phenyl)CH2—, (3,4-diF-phenyl)CH2—, (3,5-diF-phenyl)CH2—, (2,3-diCl-phenyl)CH2—, (2,4-diCl-phenyl)CH2—, (2,5-diCl-phenyl)CH2—, (2,6-diCl-phenyl)CH2—, (3,4-diCl-phenyl)CH2—, (3,5-diCl-phenyl)CH2—, (3-F-4-Cl-phenyl)CH2—, (3-F-5-Cl-phenyl)CH2—, (3-Cl-4-F-phenyl)CH2—, phenyl-CH2CH2—, (2-F-phenyl)CH2CH2—, (3-F-phenyl)CH2CH2—, (4-F-phenyl)CH2CH2—, (2-Cl-phenyl)CH2CH2—, (3-Cl-phenyl)CH2CH2—, (4-Cl-phenyl)CH2CH2—, (2,3-diF-phenyl)CH2CH2—, (2,4-diF-phenyl)CH2CH2—, (2,5-diF-phenyl)CH2CH2—, (2,6-diF-phenyl)CH2CH2—, (3,4-diF-phenyl)CH2CH2—, (3,5-diF-phenyl)CH2CH2—, (2,3-diCl-phenyl)CH2CH2—, (2,4-diCl-phenyl)CH2CH2—, (2,5-diCl-phenyl)CH2CH2—, (2,6-diCl-phenyl)CH2CH2—, (3,4-diCl-phenyl)CH2CH2—, (3,5-diCl-phenyl)CH2CH2—, (3-F-4-Cl-phenyl)CH2CH2—, (3-F-5-Cl-phenyl)CH2CH2—, or
R5 is —CH3, —CH2CH3, —CH2CH2CH3, —CH2(CH3)2, —CH2CH2CH2CH3, —CH(CH3)CH2CH3, —CH2CH(CH3)2, —CH2C(CH3)3, —CH2CH2CH2CH2CH3, —CH(CH3)CH2CH2CH3, —CH2CH(CH3)CH2CH3, —CH2CH2CH(CH3)2, —CH(CH2CH3)2, —CH2CF3, —CH2CH2CF3, —CH2CH2CH2CF3, —CH2CH2CH2CH2CF3, —CH═CH2, —CH2CH═CH2, —CH═CHCH3, cis-CH2CH═CH(CH3), trans-CH2CH═CH(CH3), trans-CH2CH═CH(C6H5), —CH2CH═C(CH3)2, cis-CH2CH═CHCH2CH3, trans-CH2CH═CHCH2CH3, cis-CH2CH2CH═CH(CH3), trans-CH2CH2CH═CH(CH3), trans-CH2CH═CHCH2 (C6H5), —C≡CH, —CH2C≡CH, —CH2C═C(CH3), —CH2C═C(C6H5) —CH2CH2C≡CH, —CH2CH2C═C(CH3), —CH2CH2C═C(C6H5) —CH2CH2CH2C≡CH, —CH2CH2CH2C═C(CH3), —CH2CH2CH2C═C(C6H5) cyclopropyl-CH2—, cyclobutyl-CH2—, cyclopentyl-CH2—, cyclohexyl-CH2—, (2-CH3-cyclopropyl)CH2—, (3-CH3-cyclobutyl) CH2—, cyclopropyl-CH2CH2—, cyclobutyl-CH2CH2—, cyclopentyl-CH2CH2—, cyclohexyl-CH2CH2—, (2-CH3-cyclopropyl)CH2CH2—, (3-CH3-cyclobutyl)CH2CH2—, phenyl-CH2—, (2-F-phenyl)CH2—, (3-F-phenyl)CH2—, (4-F-phenyl)CH2—, furanyl-CH2—, thienyl-CH2—, pyridyl-CH2—, 1-imidazolyl-CH2—, oxazolyl-CH2—, isoxazolyl-CH2—, phenyl-CH2CH2—, (2-F-phenyl)CH2CH2—, (3-F-phenyl)CH2CH2—, (4-F-phenyl)CH2CH2—, furanyl-CH2CH2—, thienyl-CH2CH2—, pyridyl-CH2CH2—, 1-imidazolyl-CH2CH2—, oxazolyl-CH2CH2—, isoxazolyl-CH2CH2—,
W is a bond, —CH2—, or —CH(CH3)—;
X is a bond;
Y is a bond, —CH2—V—, —V—, or —V—CH2—;
V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, or —N(CH3)—,
Z is phenyl 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-4-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF3O-phenyl, 3-CF3O-phenyl, 4-CF3O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholino, N-piperinyl, phenyl-CH2—, (2-F-phenyl)CH2—, (3-F-phenyl)CH2—, (4-F-phenyl)CH2—, (2-Cl-phenyl)CH2—, (3-Cl-phenyl)CH2—, (4-Cl-phenyl)CH2—, (2,3-diF-phenyl)CH2—, (2,4-diF-phenyl)CH2—, (2,5-diF-phenyl)CH2—, (2,6-diF-phenyl)CH2—, (3,4-diF-phenyl)CH2—, (3,5-diF-phenyl)CH2—, (2,3-diCl-phenyl)CH2—, (2,4-diCl-phenyl)CH2—, (2,5-diCl-phenyl)CH2—, (2,6-diCl-phenyl)CH2—, (3,4-diCl-phenyl)CH2—, (3,5-diCl-phenyl)CH2—, (3-F-4-Cl-phenyl)CH2—, (3-F-5-Cl-phenyl)CH2—, (3-Cl-4-F-phenyl)CH2—, (2-MeO-phenyl)CH2—, (3-MeO-phenyl)CH2—, (4-MeO-phenyl)CH2—, (2-Me-phenyl)CH2—, (3-Me-phenyl)CH2—, (4-Me-phenyl)CH2—, (2-MeS-phenyl)CH2—, (3-MeS-phenyl)CH2—, 4-MeS-phenyl)CH2—, (2-CF3O-phenyl)CH2—, (3-CF3O-phenyl)CH2—, (4-CF3O-phenyl)CH2—, (furanyl)CH2—, (thienyl)CH2—, (pyridyl)CH2—, (2-Me-pyridyl)CH2—, (3-Me-pyridyl)CH2—, (4-Me-pyridyl)CH2—, (1-imidazolyl)CH2—, (oxazolyl)CH2—, (isoxazolyl)CH2—, (1-benzimidazolyl)CH2—, (cyclopropyl)CH2—, (cyclobutyl)CH2—, (cyclopentyl)CH2—, (cyclohexyl)CH2—, (morpholino)CH2—, (N-pipridinyl)CH2—, phenyl-CH2CH2—, (phenyl)2CHCH2—, (2-F-phenyl)CH2CH2—, (3-F-phenyl)CH2CH2—, (4-F-phenyl)CH2CH2—, (2-Cl-phenyl)CH2CH2—, (3-Cl-phenyl)CH2CH2—, (4-Cl-phenyl)CH2CH2—, (2,3-diF-phenyl)CH2CH2—, (2,4-diF-phenyl)CH2CH2—, (2,5-diF-phenyl)CH2CH2—, (2,6-diF-phenyl)CH2CH2—, (3,4-diF-phenyl)CH2CH2—, (3,5-diF-phenyl)CH2CH2—, (2,3-diCl-phenyl)CH2CH2—, (2,4-diCl-phenyl)CH2CH2—, (2,5-diCl-phenyl)CH2CH2—, (2,6-diCl-phenyl)CH2CH2—, (3,4-diCl-phenyl)CH2CH2—, (3,5-diCl-phenyl)CH2CH2—, (3-F-4-Cl-phenyl)CH2CH2—, (3-F-5-Cl-phenyl)CH2CH2—, (3-Cl-4-F-phenyl)CH2CH2—, (2-MeO-phenyl)CH2CH2—, (3-MeO-phenyl)CH2CH2—, (4-MeO-phenyl)CH2CH2—, (2-Me-phenyl)CH2CH2—, (3-Me-phenyl)CH2CH2—, (4-Me-phenyl)CH2CH2—, (2-MeS-phenyl)CH2CH2—, (3-MeS-phenyl)CH2CH2—, (4-MeS-phenyl)CH2CH2—, (2-CF3O-phenyl)CH2CH2—, (3-CF3O-phenyl)CH2CH2—, (4-CF3O-phenyl)CH2CH2—, (furanyl)CH2CH2—, (thienyl)CH2CH2—, (pyridyl)CH2CH2—, (2-Me-pyridyl)CH2CH2—, (3-Me-pyridyl)CH2CH2—, (4-Me-pyridyl)CH2CH2—, (imidazolyl)CH2CH2—, (oxazolyl)CH2CH2—, (isoxazolyl)CH2CH2—, (benzimidazolyl)CH2CH2—, (cyclopropyl)CH2CH2—, (cyclobutyl)CH2CH2—, (cyclopentyl)CH2CH2—, (cyclohexyl)CH2CH2—, (morpholino)CH2CH2—, (N-pipridinyl)CH2CH2—,
B is
R11, at each occurrence, is independently selected from H, ═O, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH2—, (4-F-phenyl)CH2CH2—, 4-Cl-phenyl, (4-Cl-phenyl)CH2—, (4-Cl-phenyl)CH2CH2—, 4-CH3-phenyl, (4-CH3-phenyl)CH2—, (4-CH3-phenyl)CH2CH2—, 4-CF3-phenyl, (4-CF3-phenyl)CH2—, or (4-CF3-phenyl)CH2CH2—; and
alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a benzo fused radical.
6.-8. (canceled)
9. A compound of claim 4 of Formula (Ie) wherein:
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R3 is R4,
R4 is C1-C4 alkyl substituted with 0-2 R4a,
C2-C4 alkenyl substituted with 0-2 R4a,
C2-C4 alkynyl substituted with 0-2 R4a,
R4a, at each occurrence, is independently selected from is H, F, CF3,
C3-C6 cycloalkyl substituted with 0-3 R4b,
phenyl substituted with 0-3 R4b, or
5 to 6 membered heterocycle substituted with 0-3 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R5 is C1-C4 alkyl substituted with 0-3 R5b;
C2-C4 alkenyl substituted with 0-2 R5b; or
C2-C4 alkynyl substituted with 0-2 R5b;
R5b, at each occurrence, is independently selected from:
H, methyl, ethyl, propyl, butyl, CF3, OR14, ═O;
C3-C6 cycloalkyl substituted with 0-2 R5c;
phenyl substituted with 0-3 R5c; or
5 to 6 membered heterocycle substituted with 0-2 R5c;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
W is —CH2— or —CH(CH3)—;
X is a bond;
phenyl substituted with 0-2 RXb;
C3-C6 cycloalkyl substituted with 0-2 RXb; or
5 to 6 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
Y is a bond, —CH2—V—, —V—, or —V—CH2—;
V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(CH3)—, or —N(CH2CH3)—,
Z is C1-C2 alkyl substituted with 1-2 R12;
aryl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-3 R12b; or
5 to 10 membered heterocycle substituted with 0-3 R12b;
R12 is aryl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-3 R12b; or
5 to 10 membered heterocycle substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R11 is methoxy, ethoxy, propoxy, butoxy, Cl, F, ═O, NR18R19, CF3;
C1-C4 alkyl substituted with 0-1 R11a;
phenyl substituted with 0-3 R11b;
C3-C6 carbocycle substituted with 0-3 R11b; or
5 to 6 membered heterocycle substituted with 0-3 R11b;
R11a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, F, ═O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R14 is H, phenyl, benzyl, methyl, ethyl, propyl, butyl;
R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
R16, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, benzyl, phenethyl, —C(═O)—(C1-C4 alkyl) and —S(═O)2—(C1-C4 alkyl);
R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
R19, at each occurrence, is independently selected from H, methyl, and ethyl.
10. (canceled)
11. A compound of claim 2 of Formula (IIa)
or a pharmaceutically acceptable salt thereof, wherein:
R3 is —(CR7R7a)n—R4,
—(CR7R7a)n—S—(CR7R7a)m—R4,
—(CR7R7a)n—O—(CR7R7a)m—R4, or
—(CR7R7a)n—N(R7b)—(CR7R7a)m—R4;
n is 0, 1, or 2;
m is 0, 1, or 2;
R3a is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, or butoxy;
R4 is H, OH, OR14a,
C1-C4 alkyl substituted with 0-2 R4a,
C2-C4 alkenyl substituted with 0-2 R4a,
C2-C4 alkynyl substituted with 0-2 R4a,
C3-C6 cycloalkyl substituted with 0-3 R4b,
aryl substituted with 0-3 R4b, or
5 to 10 membered heterocycle substituted with 0-3 R4b;
R4a, at each occurrence, is independently selected from is H, F, Cl, Br, I CF3,
C3-C10 carbocycle substituted with 0-3 R4b,
aryl substituted with 0-3 R4b, or
5 to 10 membered heterocycle substituted with 0-3 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R5 is H, OR14;
C1-C6 alkyl substituted with 0-3 R5b;
C2-C6 alkenyl substituted with 0-3 R5b;
C2-C6 alkynyl substituted with 0-3 R5b;
C3-C10 carbocycle substituted with 0-3 R5c;
aryl substituted with 0-3 R5c; or
5 to 10 membered heterocycle substituted with 0-3R5c;
R5a is H, OH, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, or C2-C4 alkenyloxy;
R5b, at each occurrence, is independently selected from:
H, C1-C6 alkyl, CF3, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16;
C3-C10 carbocycle substituted with 0-3 R5c;
aryl substituted with 0-3 R5c; or
5 to 10 membered heterocycle substituted with 0-3 R5c;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R6 is H, methyl, or ethyl;
R7, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, and C1-C4 alkyl;
R7a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, phenyl and C1-C4 alkyl;
R7b is independently selected from H, methyl, ethyl, propyl, and butyl;
W is —(CR8R8a)p—;
p is 0, 1, or 2;
R8 and R8a, at each occurrence, are independently selected from H, F, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl and C3-C6 cycloalkyl;
X is a bond;
aryl substituted with 0-3 RXb;
C3-C10 carbocycle substituted with 0-2 RXb; or
5 to 10 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
Y is a bond or —(CR9R9a)t—V—(CR9R9a)u—;
t is 0, 1, or 2;
u is 0, 1, or 2;
R9 and R9a, at each occurrence, are independently selected from H, F, C1-C4 alkyl or C3-C6 cycloalkyl;
V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —N(R19)—, C(═O)NR19b—, NR19bC(═O)—, —NR19bS(═O)2—, —S(═O)2NR19b—, —NR19bS(═O)—, or —S(═O)NR19b—;
Z is C1-C3 alkyl substituted with 1-2 R12;
aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle substituted with 0-3 R12b;
R12 is C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
B is
R11, at each occurrence, is independently selected from
C1-C4 alkoxy, Cl, F, ═O, NR18R19, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, CF3;
C1-C6 alkyl substituted with 0-1 R11a;
aryl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; or
5 to 10 membered heterocycle substituted with 0-3 R1b;
alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle or a benzo fused radical;
R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R14 is H, phenyl, benzyl, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl);
R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl);
R17 is H, aryl, (aryl)CH2—, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
R18, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl); and
R19, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, —C(═O)-(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl); and
R19b is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or phenethyl.
12. A compound of claim 11 of Formula (IIb) wherein:
or pharmaceutically acceptable salt or prodrug thereof, wherein:
R3 is R4,
n is 0 or 1;
m is 0 or 1;
R4 is H, OH,
C1-C4 alkyl substituted with 0-2 R4a,
C2-C4 alkenyl substituted with 0-2 R4a,
C2-C4 alkynyl substituted with 0-1 R4a,
C3-C6 cycloalkyl substituted with 0-3 R4b,
aryl substituted with 0-3 R4b, or
5 to 10 membered heterocycle substituted with 0-3 R4b;
R4a, at each occurrence, is independently selected from is H, F, Cl, CF3,
C3-C6 cycloalkyl substituted with 0-3 R4b,
phenyl substituted with 0-3 R4b, or
5 to 6 membered heterocycle substituted with 0-3 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R5 is H, OR14;
C1-C4 alkyl substituted with 0-3 R5b;
C2-C4 alkenyl substituted with 0-2 R5b; or
C2-C4 alkynyl substituted with 0-2 R5b;
R5b, at each occurrence, is independently selected from:
H, methyl, ethyl, propyl, butyl, CF3, OR14, ═O;
C3-C6 cycloalkyl substituted with 0-2 R5c;
phenyl substituted with 0-3 R5c; or
5 to 6 membered heterocycle substituted with 0-2 R5c;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
W is a bond, —CH2—, —CH(CH3)—, —CH2CH2— or —CH(CH3)CH2—;
X is a bond;
phenyl substituted with 0-2 RXb;
C3-C6 cycloalkyl substituted with 0-2 RXb; or
5 to 6 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
Y is a bond, —CH2—V—, —V—, or —V—CH2—;
V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(CH3)—, or —N(CH2CH3)—,
Z is C1-C2 alkyl substituted with 1-2 R12;
aryl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-3 R12b; or
5 to 10 membered heterocycle substituted with 0-3 R12b;
R12 is aryl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-3 R12b; or
5 to 10 membered heterocycle substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
B is
R11, at each occurrence, is independently selected from
C1-C4 alkoxy, Cl, F, ═O, NR18R19, C(═O)R17, C(═O)OR17, CF3;
C1-C6 alkyl substituted with 0-1 R11a;
phenyl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; or
5 to 10 membered heterocycle substituted with 0-3 R11b;
alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a benzo fused radical;
R11a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, F, ═O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R14 is H, phenyl, benzyl, C1-C4 alkyl, or C2-C4 alkoxyalkyl;
R15, at each occurrence, is independently selected from H, C1-C4 alkyl, benzyl, phenethyl, —C(═O)—(C1-C4 alkyl) and —S(═O)2—(C1-C4 alkyl);
R16, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, benzyl, phenethyl, —C(═O)—(C1-C4 alkyl) and —S(═O)2—(C1-C4 alkyl);
R17 is H, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl, (4-methylphenyl)methyl, (4-trifluorophenyl)methyl, methyl, ethyl, propyl, butyl, methoxymethyl, methyoxyethyl, ethoxymethyl, or ethoxyethyl;
R18 at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
R19, at each occurrence, is independently selected from H, methyl, and ethyl.
13.-23. (canceled)
24. A pharmaceutical composition comprising a compound of claim 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
25. A method for the treatment of Alzheimer's Disease neurological disorders associated with β-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 2 or a pharmaceutically acceptable salt thereof.
26. A method for the treatment of Alzheimer's Disease associated with β-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 3 or a pharmaceutically acceptable salt thereof.
27. A method for the treatment of Alzheimer's Disease associated with β-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 4 or a pharmaceutically acceptable salt thereof.
28. A method for the treatment of Alzheimer's Disease associated with β-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 5 or a pharmaceutically acceptable salt thereof.
29. A method for the treatment of Alzheimer's Disease associated with β-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 9 or a pharmaceutically acceptable salt thereof.
30. A method for the treatment of Alzheimer's Disease associated with β-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 11 or a pharmaceutically acceptable salt thereof.
31. A method for the treatment of neurological disorders associated with β-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a metalloprotease inhibitor of claim 2 which inhibits γ-secretase activity.
32. The method of claim 31 wherein the metalloprotease inhibitor is a hydroxamic acid.
33. The method of claim 31 wherein the metalloprotease inhibitor is a hydroxamic acid with an IC50 value of less than 10 μM in the Aβ immunoprecipitation assay.
34. (canceled)
35. A method for the treatment of Alzheimer's Disease comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 12 or a pharmaceutically acceptable salt thereof.
36. A compound of Formula (Ie),
or a pharmaceutically acceptable salt thereof,
wherein:
R3 is C1-C4 alkyl substituted with 0-2 R4a,
C2-C4 alkenyl substituted with 0-2 R4a,
C2-C4 alkynyl substituted with 0-2 R4a,
R4a, at each occurrence, is independently selected from is H, F, CF3,
C3-C6 cycloalkyl substituted with 0-3 R4b,
phenyl substituted with 0-3 R4b, or
5 to 6 membered heterocycle substituted with 0-3 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R5 is C1-C4 alkyl substituted with 0-3 R5b;
C2-C4 alkenyl substituted with 0-2 R5b; or
C2-C4 alkynyl substituted with 0-2 R5b;
R5b, at each occurrence, is independently selected from:
H, methyl, ethyl, propyl, butyl, CF3, OR14, ═O;
C3-C6 cycloalkyl substituted with 0-2 R5c;
phenyl substituted with 0-3 R5c; or
5 to 6 membered heterocycle substituted with 0-2 R5c;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
W is a bond, —CH2— or —CH(CH3)—;
X is a bond;
phenyl substituted with 0-2 RXb;
C3-C6 cycloalkyl substituted with 0-2 RXb; or
5 to 6 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
Y is a bond, —CH2—V—, —V—, or —V—CH2—;
V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(CH3)—, or —N(CH2CH3)—,
Z is C1-C2 alkyl substituted with 1-2 R12;
aryl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-3 R12b; or
5 to 10 membered heterocycle substituted with 0-3 R12b;
R12 is aryl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-3 R12b; or
5 to 10 membered heterocycle substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R11, at each occurrence, is independently selected from
C1-C4 alkoxy, Cl, F, ═O, NR18R19, C(═O)R17, C(═O)OR17, CF3;
C1-C4 alkyl substituted with 0-1 R11a;
phenyl substituted with 0-3 R11b;
C3-C6 carbocycle substituted with 0-3 R11b; or
5 to 6 membered heterocycle substituted with 0-3 R11b;
alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a benzo fused radical;
R11a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, F, ═O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R14 is H, phenyl, benzyl, methyl, ethyl, propyl, butyl;
R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; and
R16, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, benzyl, phenethyl, —C(═O)—(C1-C4 alkyl) and —S(═O)2—(C1-C4 alkyl).
37. A compound of claim 36 of Formula (Ie):
or a pharmaceutically acceptable salt thereof,
wherein:
R3 is C1-C4 alkyl substituted with 0-1 R4a,
C2-C4 alkenyl substituted with 0-1 R4a,
C2-C4 alkynyl substituted with 0-1 R4a,
R4a is C3-C6 cycloalkyl substituted with 0-3 R4b, or phenyl substituted with 0-3 R4b;
R4b, at each occurrence, is independently selected from H, Cl, F, or methyl;
R5 is C1-C4 alkyl substituted with 0-1 R5b;
C2-C4 alkenyl substituted with 0-1 R5b; or
C2-C4 alkynyl substituted with 0-1 R5b;
R5b is H or C3-C6 cycloalkyl substituted with 0-2 R5c;
R5c, at each occurrence, is independently selected from H, Cl, F, and methyl;
W is a bond or —CH2—;
X is a bond;
phenyl substituted with 0-1 RXb;
C3-C6 cycloalkyl substituted with 0-2 RXb; or
pyridyl substituted with 0-1 RXb;
RXb is H, Cl, F, CF3, SCH3, methyl, methoxy, C1-C2 haloalkyl, or C1-C2 haloalkoxy;
Y is a bond or —V—;
V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(CH3)—, or —N(CH2CH3)—,
Z is C1-C2 alkyl substituted with 1-2 R12;
aryl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-3 R12b; or
5 to 6 membered heterocycle substituted with 0-3 R12b;
R12 is aryl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-3 R12b; or
5 to 6 membered heterocycle substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R11 at each occurrence, is independently selected from
C1-C4 alkoxy, Cl, F, ═O, NR18R19, C(═O)R17, C(═O)OR17, CF3;
C1-C4 alkyl substituted with 0-1 R11a;
phenyl substituted with 0-3 R11b;
C3-C6 carbocycle substituted with 0-3 R11b; or
5 to 6 membered heterocycle substituted with 0-3 R11b;
alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a benzo fused radical;
R11a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, F, ═O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R14 is H, phenyl, benzyl, methyl, ethyl, propyl, butyl;
R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; and
R16, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, benzyl, phenethyl, —C(═O)—(C1-C4 alkyl) and —S(═O)2—(C1-C4 alkyl).
38. A compound of claim 36 of Formula (Ie)
or a pharmaceutically acceptable salt thereof,
wherein:
R3 is C2-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl;
R5 is C1-C4 alkyl substituted with 0-1 R5b;
R5b is H, cyclopropyl, (methyl)cyclopropyl-, (methyl)cyclobutyl-, cyclobutyl, cyclopentyl, or cyclohexyl;
W is a bond or —CH2—;
X is a bond;
Y is a bond;
Z is methyl substituted with 1-2 R12;
ethyl substituted with 1-2 R12;
phenyl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-3 R12b; or
5 to 6 membered heterocycle substituted with 0-3 R12b;
R12 is phenyl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-3 R12b; or
5 to 6 membered heterocycle substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R11, at each occurrence, is independently selected from
C1-C4 alkoxy, Cl, F, ═O, NR18R19, C(═O)R17, C(═O)OR17, CF3;
C1-C4 alkyl substituted with 0-1 R11a;
phenyl substituted with 0-3 R11b;
C3-C6 carbocycle substituted with 0-3 R11b; or
5 to 6 membered heterocycle substituted with 0-3 R11b;
alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a benzo fused radical;
R11a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, F, ═O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; and
R16, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, benzyl, phenethyl, —C(═O)—(C1-C4 alkyl) and —S(═O)2—(C1-C4 alkyl).
39. A compound of claim 36 of Formula (Ie)
or a pharmaceutically acceptable salt thereof,
wherein:
R3 is —CH2CH2CH3, —CH2CH2CH2CH3, —CH2(CH3)2, —CH(CH3)CH2CH3, —CH2CH(CH3)2, —CH2C(CH3)3, —CH═CH2, —CH2CH═CH2, —CH2C(CH3)═CH2, —CH2CH═C(CH3)2, —CH2CH2CH═CH2, —CH2CH2C(CH3)═CH2, —CH2CH2CH═C(CH3)2, cis-CH2CH═CH(CH3), cis-CH2CH2CH═CH(CH3), trans-CH2CH═CH(CH3), trans-CH2CH2CH═CH(CH3), cyclopropyl-CH2—, cyclobutyl-CH2—, cyclopentyl-CH2—, cyclohexyl-CH2—, cyclopropyl-CH2CH2—, cyclobutyl-CH2CH2—, cyclopentyl-CH2CH2—, cyclohexyl-CH2CH2—, phenyl-CH2—, (3,5-diF-phenyl)CH2—, phenyl-CH2CH2—, or (3,5-diF-phenyl)CH2CH2—;
R5 is —CH3, —CH2CH3, —CH2CH2CH3, —CH2(CH3)2, —CH2CH2CH2CH3, —CH(CH3)CH2CH3, —CH2CH(CH3)2, —CH2C(CH3)3, —CH2CH2CH2CH2CH3, —CH(CH3)CH2CH2CH3, —CH2CH(CH3)CH2CH3, —CH2CH2CH(CH3)2, —CH(CH2CH3)2, cyclopropyl-CH2—, cyclobutyl-CH2—, cyclopentyl-CH2—, cyclohexyl-CH2—, (2-CH3-cyclopropyl)CH2—, (3-CH3-cyclobutyl)CH2—, cyclopropyl-CH2CH2—, cyclobutyl-CH2CH2—, cyclopentyl-CH2CH2—, cyclohexyl-CH2CH2—, (2-CH3-cyclopropyl)CH2CH2—, or (3-CH3-cyclobutyl)CH2CH2—;
W is a bond or —CH2—;
X is a bond;
Y is a bond;
Z is phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-4-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF3O-phenyl, 3-CF3O-phenyl, 4-CF3O-phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl-CH2—, (2-F-phenyl)CH2—, (3-F-phenyl)CH2—, (4-F-phenyl)CH2—, (2-Cl-phenyl)CH2—, (3-Cl-phenyl)CH2—, (4-Cl-phenyl)CH2—, (2,3-diF-phenyl)CH2—, (2,4-diF-phenyl)CH2—, (2,5-diF-phenyl)CH2—, (2,6-diF-phenyl)CH2—, (3,4-diF-phenyl)CH2—, (3,5-diF-phenyl)CH2—, (2,3-diCl-phenyl)CH2—, (2,4-diCl-phenyl)CH2—, (2,5-diCl-phenyl)CH2—, (2,6-diCl-phenyl)CH2—, (3,4-diCl-phenyl)CH2—, (3,5-diCl-phenyl)CH2—, (3-F-4-Cl-phenyl)CH2—, (3-F-5-Cl-phenyl)CH2—, (3-Cl-4-F-phenyl)CH2—, (2-MeO-phenyl)CH2—, (3-MeO-phenyl)CH2—, (4-MeO-phenyl)CH2—, (2-Me-phenyl)CH2—, (3-Me-phenyl)CH2—, (4-Me-phenyl)CH2—, (2-MeS-phenyl)CH2—, (3-MeS-phenyl)CH2—, 4-MeS-phenyl)CH2—, (2-CF3O-phenyl)CH2—, (3-CF3O-phenyl)CH2—, (4-CF3O-phenyl)CH2—, (cyclopropyl)CH2—, (cyclobutyl)CH2—, (cyclopentyl)CH2—, (cyclohexyl)CH2—, phenyl-CH2CH2—, (phenyl)2CHCH2—, (2-F-phenyl)CH2CH2—, (3-F-phenyl)CH2CH2—, (4-F-phenyl)CH2CH2—, (2-Cl-phenyl)CH2CH2—, (3-Cl-phenyl)CH2CH2—, (4-Cl-phenyl)CH2CH2—, (2,3-diF-phenyl)CH2CH2—, (2,4-diF-phenyl)CH2CH2—, (2,5-diF-phenyl)CH2CH2—, (2,6-diF-phenyl)CH2CH2—, (3,4-diF-phenyl)CH2CH2—, (3,5-diF-phenyl)CH2CH2—, (2,3-diCl-phenyl)CH2CH2—, (2,4-diCl-phenyl)CH2CH2—, (2,5-diCl-phenyl)CH2CH2—, (2,6-diCl-phenyl)CH2CH2—, (3,4-diCl-phenyl)CH2CH2—, (3,5-diCl-phenyl)CH2CH2—, (3-F-4-Cl-phenyl)CH2CH2—, (3-F-5-Cl-phenyl)CH2CH2—, (3-Cl-4-F-phenyl)CH2CH2—, (2-MeO-phenyl)CH2CH2—, (3-MeO-phenyl)CH2CH2—, (4-MeO-phenyl)CH2CH2—, (2-Me-phenyl)CH2CH2—, (3-Me-phenyl)CH2CH2—, (4-Me-phenyl)CH2CH2—, (2-MeS-phenyl)CH2CH2—, (3-MeS-phenyl)CH2CH2—, (4-MeS-phenyl)CH2CH2—, (2-CF3O-phenyl)CH2CH2—, (3-CF3O-phenyl)CH2CH2—, (4-CF3O-phenyl)CH2CH2—, (cyclopropyl)CH2CH2—, (cyclobutyl)CH2CH2—, (cyclopentyl)CH2CH2—, or (cyclohexyl)CH2CH2.
R11, at each occurrence, is independently selected from
C1-C4 alkoxy, Cl, F, ═O, NR18R19, C(═O)R17, C(═O)OR17, CF3;
C1-C4 alkyl substituted with 0-1 R11a;
phenyl substituted with 0-3 R11b;
C3-C6 carbocycle substituted with 0-3 R11b; or
5 to 6 membered heterocycle substituted with 0-3 R11b;
alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a benzo fused radical;
R11a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, F, ═O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy.
40. A pharmaceutical composition comprising a compound of claim 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
41. A pharmaceutical composition comprising a compound of claim 4 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
42. A pharmaceutical composition comprising a compound of claim 5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
43. A pharmaceutical composition comprising a compound of claim 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
44. A pharmaceutical composition comprising a compound of claim 11 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
45. A pharmaceutical composition comprising a compound of claim 12 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
46. A pharmaceutical composition comprising a compound of claim 36 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
47. A pharmaceutical composition comprising a compound of claim 37 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
48. A pharmaceutical composition comprising a compound of claim 38 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
49. A pharmaceutical composition comprising a compound of claim 39 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
50. A method for the treatment of Alzheimer's Disease comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 36 or a pharmaceutically acceptable salt thereof.
51. A method for the treatment of Alzheimer's Disease comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 37 or a pharmaceutically acceptable salt thereof.
52. A method for the treatment of Alzheimer's Disease comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 38 or a pharmaceutically acceptable salt thereof.
53. A method for the treatment of Alzheimer's Disease comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 39 or a pharmaceutically acceptable salt thereof.
Description
    RELATED CROSS-REFERENCES
  • [0001]
    This application is a continuation of U.S. patent application Ser. No. 11/175,644, filed Jul. 6, 2005, which is a divisional of U.S. patent application Ser. No. 10/285,776, filed Nov. 1, 2002, which is a divisional of U.S. patent application Ser. No. 09/506,360, filed Feb. 17, 2000, now U.S. Pat. No. 6,794,381, issued Sep. 21, 2004, which is a continuation-in-part of U.S. patent application Ser. No. 09/370,089, filed Aug. 6, 1999, now abandoned, Provisional Application Ser. No. 60/095,698, filed Aug. 7, 1998 (expired), and Provisional U.S. Patent Application Ser. No. 60/120,227, filed Feb. 15, 1999 (expired), and Provisional Application Ser. No. 60/113,558, filed Dec. 23, 1998 (expired); the disclosures of which are hereby incorporated by reference in their entirety.
  • FIELD OF THE INVENTION
  • [0002]
    This invention relates to novel lactams having drug and bio-affecting properties, their pharmaceutical compositions and methods of use. These novel compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Aβ-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein. More particularly, the present invention relates to the treatment of neurological disorders related to β-amyloid production such as Alzheimer's disease and Down's Syndrome.
  • BACKGROUND OF THE INVENTION
  • [0003]
    Alzheimer's disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, temporal and local orientation, cognition, reasoning, judgment and emotional stability. AD is a common cause of progressive dementia in humans and is one of the major causes of death in the United States. AD has been observed in all races and ethnic groups worldwide, and is a major present and future health problem. No treatment that effectively prevents AD or reverses the clinical symptoms and underlying pathophysiology is currently available (for review, Dennis J. Selkoe; Cell Biology of the amyloid (beta)-protein precursor and the mechanism of Alzheimer's disease, Annu Rev Cell Biol, 1994, 10: 373-403).
  • [0004]
    Histopathological examination of brain tissue derived upon autopsy or from neurosurgical specimens in effected individuals revealed the occurrence of amyloid plaques and neurofibrillar tangles in the cerebral cortex of such patients. Similar alterations were observed in patients with Trisomy 21 (Down's Syndrome) and hereditary cerebral hemorrhage with amyloidosis of the Dutch-type. Neurofibrillar tangles are nonmembrane-bound bundles of abnormal proteinaceous filaments and biochemical and immunochemical studies led to the conclusion that their principle protein subunit is an altered phosphorylated form of the tau protein (reviewed in Selkoe, 1994).
  • [0005]
    Biochemical and immunological studies revealed that the dominant proteinaceous component of the amyloid plaque is an approximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acids. This protein was designated Aβ, β-amyloid peptide, and sometimes β/A4; referred to herein as Aβ. In addition to deposition of Aβ in amyloid plaques, Aβ is also found in the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, venules. Aβ was first purified, and a partial amino acid reported, in 1984 (Glenner and Wong, Biochem. Biophys. Res. Commun. 120: 885-890). The isolation and sequence data for the first 28 amino acids are described in U.S. Pat. No. 4,666,829.
  • [0006]
    Compelling evidence accumulated during the last decade revealed that Aβ is an internal polypeptide derived from a type 1 integral membrane protein, termed β amyloid precursor protein (APP). β APP is normally produced by many cells both in vivo and in cultured cells, derived from various animals and humans. Aβ is derived from cleavage of β APP by as yet unknown enzyme (protease) system(s), collectively termed secretases.
  • [0007]
    The existence of at least four proteolytic activities has been postulated. They include β secretase(s), generating the N-terminus of Aβ, a secretase(s) cleaving around the 16/17 peptide bond in Aβ, and γ secretases, generating C-terminal Aβ fragments ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides.
  • [0008]
    Several lines of evidence suggest that abnormal accumulation of Aβ plays a key role in the pathogenesis of AD. Firstly, Aβ is the major protein found in amyloid plaques. Secondly, Aβ is neurotoxic and may be causally related to neuronal death observed in AD patients. Thirdly, missense DNA mutations at position 717 in the 770 isoform of β APP can be found in effected members but not unaffected members of several families with a genetically determined (familiar) form of AD. In addition, several other β APP mutations have been described in familiar forms of AD. Fourthly, similar neuropathological changes have been observed in transgenic animals overexpressing mutant forms of human b APP. Fifthly, individuals with Down's syndrome have an increased gene dosage of β APP and develop early-onset AD. Taken together, these observations strongly suggest that Aβ depositions may be causally related to the AD.
  • [0009]
    It is hypothesized that inhibiting the production of Aβ will prevent and reduce neurological degeneration, by controlling the formation of amyloid plaques, reducing neurotoxicity and, generally, mediating the pathology associated with Aβ production. One method of treatment methods would therefore be based on drugs that inhibit the formation of Aβ in vivo.
  • [0010]
    Methods of treatment could target the formation of Aβ through the enzymes involved in the proteolytic processing of b amyloid precursor protein. Compounds that inhibit b or g secretase activity, either directly or indirectly, could control the production of Aβ. Advantageously, compounds that specifically target g secretases, could control the production of Aβ. Such inhibition of β or γ secretases could thereby reduce production of Aβ, which, thereby, could reduce or prevent the neurological disorders associated with Aβ protein.
  • [0011]
    PCT publication number WO 96/29313 discloses the general formula:
    covering metalloprotease inhibiting compounds useful for the treatment of diseases associated with excess and/or unwanted matrix metalloprotease activity, particularly collagenase and or stromelysin activity.
  • [0012]
    Compounds of general formula:
    are disclosed in PCT publication number WO 95/22966 relating to matrix metalloprotease inhibitors. The compounds of the invention are useful for the treatment of conditions associated with the destruction of cartilage, including corneal ulceration, osteoporosis, periodontitis and cancer.
  • [0013]
    European Patent Application number EP 0652009A1 relates to the general formula:
    and discloses compounds that are protease inhibitors that inhibit Aβ production.
  • [0014]
    U.S. Pat. No. 5,703,129 discloses the general formula:
    which covers 5-amino-6-cyclohexyl-4-hydroxy-hexanamide derivatives that inhibit Aβ production and are useful in the treatment of Alzheimer's disease.
  • [0015]
    None of the above references teaches or suggests the compounds of the present invention which are described in detail below.
  • SUMMARY OF THE INVENTION
  • [0016]
    One object of the present invention is to provide novel compounds which are useful as inhibitors of the production of Aβ protein or pharmaceutically acceptable salts or prodrugs thereof.
  • [0017]
    It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
  • [0018]
    It is another object of the present invention to provide a method for treating degenerative neurological disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
  • [0019]
    These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of Formula (I):
    or pharmaceutically acceptable salt or prodrug forms thereof, wherein R3, R3a, R5, R5a, R6, A, Q, B, W, X, Y, and Z are defined below, are effective inhibitors of the production of Aβ.
  • DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
  • [0020]
    Thus, in a first embodiment, the present invention provides a novel compound of Formula (I):
    • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
    • A is O or S;
    • Q is —OR1 or —NR1R2;
    • R1, at each occurrence, is independently selected from:
      • H;
      • C1-C6 alkyl substituted with 0-3 R1a;
      • C2-C6 alkenyl substituted with 0-3 R1a;
      • C3-C10 carbocycle substituted with 0-3 R1b;
      • C6-C10 aryl substituted with 0-3 R1b; and
      • 5 to 10 membered heterocycle substituted with 0-3 R1b;
    • R1a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3;
      • C3-C10 carbocycle substituted with 0-3 R1b;
      • C6-C10 aryl substituted with 0-3 R1b; and
      • 5 to 6 membered heterocycle substituted with 0-3 R1b;
    • R1b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • R2 is independently selected from H, NH2, OH, C1-C6 alkyl, C1-C6 alkoxy, phenoxy, benzyloxy, C3-C10 carbocycle, C6-C10 aryl and 5 to 10 membered heterocycle;
    • R3 is —(CR7R7a)n—R4,
      • —(CR7R7a)n—S—(CR7R7a)m—R4,
      • —(CR7R7a)n—O—(CR7R7a)m—R4,
      • —(CR7R7a)n—N(R7b)—(CR7R7a)m—R4,
      • —(CR7R7a)n—S(═O)—(CR7R7a)m—R4,
      • —(CR7R7a)n—S(═O)2—(CR7R7a)m—R4,
      • —(CR7R7a)n—C(═O)—(CR7R7a)m—R4,
      • —(CR7R7a)n—N(R7b)C(═O)—(CR7R7a)m—R4,
      • —(CR7R7a)n—C(═O)N(R7b)—(CR7R7a)m—R4,
      • —(CR7R7a)n—N(R7b)—S(═O)2—(CR7R7a)m—R4, or
      • —(CR7R7a)n—S(═O)2N(R7b)—(CR7R7a)m—R4;
    • n is 0, 1, 2, or 3;
    • m is 0, 1, 2, or 3;
    • R3a is H, OH, C1-C4 alkyl, C1-C4 alkoxy, or C2-C4 alkenyloxy;
    • R4 is H, OH, OR14a,
      • C1-C6 alkyl substituted with 0-3 R4a,
      • C2-C6 alkenyl substituted with 0-3 R4a,
      • C2-C6 alkynyl substituted with 0-3 R4a,
      • C3-C10 carbocycle substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, or
      • 5 to 10 membered heterocycle substituted with 0-3 R4b;
    • R4a, at each occurrence, is independently selected from is H, F, Cl, Br, I, CF3,
      • C3-C10 carbocycle substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, or
      • 5 to 10 membered heterocycle substituted with 0-3 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
    • R5 is H, OR14;
      • C1-C6 alkyl substituted with 0-3 R5b;
      • C1-C6 alkoxy substituted with 0-3 R5b;
      • C2-C6 alkenyl substituted with 0-3 R5b;
      • C2-C6 alkynyl substituted with 0-3 R5b;
      • C3-C10 carbocycle substituted with 0-3 R5c;
      • C6-C10 aryl substituted with 0-3 R5c; or
      • 5 to 10 membered heterocycle substituted with 0-3R5c;
    • R5a is H, OH, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, or C2-C4 alkenyloxy;
    • R5b, at each occurrence, is independently selected from:
      • H, C1-C6 alkyl, CF3, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16;
      • C3-C10 carbocycle substituted with 0-3 R5c;
      • C6-C10 aryl substituted with 0-3 R5c; or
      • 5 to 10 membered heterocycle substituted with 0-3 R5c;
    • R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
    • R6 is H;
      • C1-C6 alkyl substituted with 0-3 R6a;
      • C3-C10 carbocycle substituted with 0-3 R6b; or
      • C6-C10 aryl substituted with 0-3R6b;
    • R6a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, phenyl or CF3;
    • R6b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • R7, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, and C1-C4 alkyl;
    • R7a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, aryl and C1-C4 alkyl;
    • R7b is independently selected from H and C1-C4 alkyl;
    • W is —(CR8R8a)p—;
    • p is 0, 1, 2, 3, or 4;
    • R8 and R8a, at each occurrence, are independently selected from H, F, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and C3-C8 cycloalkyl;
    • X is a bond;
      • C6-C10 aryl substituted with 0-3 RXb;
      • C3-C10 carbocycle substituted with 0-3 RXb; or
      • 5 to 10 membered heterocycle substituted with 0-2 RXb;
    • RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
    • Y is a bond or —(CR9R9a)t—V—(CR9R9a)u—;
    • t is 0, 1, 2, or 3;
    • u is 0, 1, 2, or 3;
    • R9 and R9a, at each occurrence, are independently selected from H, F, C1-C6 alkyl or C3-C8 cycloalkyl;
    • V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —N(R19)—, —C(═O)NR19b—, —NR19bC(═O)—, —NR19bS(═O)2—, —S(═O)2NR19b—, —NR19bS(═O)—, —S(═O)NR19b—, —C(═O)O—, or —OC(═O)—;
    • Z is C1-C4 alkyl substituted with 0-3 R12b;
      • C1-C3 alkyl substituted with 1-2 R12;
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12 is C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
    • B is a 5 to 10 membered lactam or thiolactam,
      • wherein the lactam or thiolactam is saturated, partially saturated or unsaturated;
      • wherein each additional lactam carbon or thiolactam carbon is substituted with 0-2 R11; and,
      • optionally, the lactam or thiolactam contains a heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)2—, and —N(R10)—;
    • R10 is H, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, S(═O)2R17;
      • C1-C6 alkyl substituted with 0-2 R10a;
      • C6-C10 aryl substituted with 0-4 R10b;
      • C3-C10 carbocycle substituted with 0-3 R10b; or
      • 5 to 10 membered heterocycle optionally substituted with 0-3 R10b;
    • R10a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or aryl substituted with 0-4 R10b;
    • R10b, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
    • R11, at each occurrence, is independently selected from
      • C1-C4 alkoxy, Cl, F, Br, I, ═O, CN, NO2, NR18R19, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, CF3;
      • C1-C6 alkyl substituted with 0-1 R11a;
      • C6-C10 aryl substituted with 0-3 R11b;
      • C3-C10 carbocycle substituted with 0-3 R11b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R11b;
    • alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle or a benzo fused radical;
    • R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
    • R1b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
    • R14, at each occurrence, is independently selected from H, phenyl, benzyl, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
    • R14a is H, phenyl, benzyl, or C1-C4 alkyl;
    • R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl);
    • R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl);
    • R17 is H, aryl, aryl-CH2—, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
    • R18, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl); and
    • R19, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl); and
    • R19b is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or phenethyl.
  • [0137]
    [2] In a preferred embodiment the present provides
    • A is O;
    • Q is —NR1R2;
    • R1, at each occurrence, is independently selected from:
      • H;
      • C1-C6 alkyl substituted with 0-3 R1a;
      • C2-C6 alkenyl substituted with 0-3 R1a;
    • R1a, at each occurrence, is independently selected from H, OR14, F, ═O, NR15R16, CF3;
      • C3-C6 cycloalkyl substituted with 0-3 R1b;
      • phenyl substituted with 0-3 R1b; and
      • 5 to 6 membered heterocycle substituted with 0-3 R1b;
    • R1b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • R2 is independently selected from H, NH2, OH, C1-C6 alkyl, C1-C6 alkoxy, phenoxy, and benzyloxy;
    • R3 is —(CR7R7a)n—R4,
      • —(CR7R7a)n—S—(CR7R7a)m—R4,
      • —(CR7R7a)n—O—(CR7R7a)m—R4,
      • —(CR7R7a)n—N(R7b)—(CR7R7a)m—R4,
      • —(CR7R7a)n—S(═O)—(CR7R7a)m—R4,
      • —(CR7R7a)n—S(═O)2—(CR7R7a)m—R4,
      • —(CR7R7a)n—C(═O)—(CR7R7a)m—R4,
      • —(CR7R7a)n—NHC(═O)—(CR7R7a)m—R4,
      • —(CR7R7a)n—C(═O)NH—(CR7R7a)m—R4,
      • —(CR7R7a)n—NHS(═O)2—(CR7R7a)m—R4, or
      • —(CR7R7a)n—S(═O)2NH—(CR7R7a)m—R4;
    • n is 0, 1, 2, or 3;
    • m is 0, 1, 2, or 3;
    • R3a is H, OH, C1-C4 alkyl, C1-C4 alkoxy, or C2-C4 alkenyloxy;
    • R4 is H, OH, OR14a,
      • C1-C6 alkyl substituted with 0-3 R4a,
      • C2-C6 alkenyl substituted with 0-3 R4a,
      • C2-C6 alkynyl substituted with 0-3 R4a,
      • C3-C10 carbocycle substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, or
      • 5 to 10 membered heterocycle substituted with 0-3 R4b;
    • R4a, at each occurrence, is independently selected from is H, F, Cl, Br, I, CF3,
      • C3-C10 carbocycle substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, or
      • 5 to 10 membered heterocycle substituted with 0-3 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • R5 is H, OR14;
      • C1-C6 alkyl substituted with 0-3 R5b;
      • C1-C6 alkoxy substituted with 0-3 R5b;
      • C2-C6 alkenyl substituted with 0-3 R5b;
      • C2-C6 alkynyl substituted with 0-3 R5b;
      • C3-C10 carbocycle substituted with 0-3 R5c;
      • C6-C10 aryl substituted with 0-3 R5c; or
      • 5 to 10 membered heterocycle substituted with 0-3R5c;
    • R5a is H, OH, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, or C2-C4 alkenyloxy;
    • R5b, at each occurrence, is independently selected from:
      • H, C1-C6 alkyl, CF3, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16;
      • C3-C10 carbocycle substituted with 0-3 R5c;
      • C6-C10 aryl substituted with 0-3 R5c; or
      • 5 to 10 membered heterocycle substituted with 0-3 R5c;
    • R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • R6 is H;
      • C1-C6 alkyl substituted with 0-3 R6a;
      • C3-C6 carbocycle substituted with 0-3 R6b; or
      • C6-C10 aryl substituted with 0-3R6b;
    • R6a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, phenyl or CF3;
    • R6b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • R7, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, and C1-C4 alkyl;
    • R7a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, aryl and C1-C4 alkyl;
    • R7b is independently selected from H and C1-C4 alkyl;
    • W is —(CR8R8a)p—;
    • p is 0, 1, 2, 3, or 4;
    • R8 and R8a, at each occurrence, are independently selected from H, F, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and C3-C8 cycloalkyl;
    • X is a bond;
      • C6-C10 aryl substituted with 0-3 RXb;
      • C3-C10 carbocycle substituted with 0-3 RXb; or
      • 5 to 10 membered heterocycle substituted with 0-2 RXb;
    • RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • Y is a bond or —(CR9R9a)t—V—(CR9R9a)u—;
    • t is 0, 1, 2, or 3;
    • u is 0, 1, 2, or 3;
    • R9 and R9a, at each occurrence, are independently selected from H, F, C1-C6 alkyl or C3-C8 cycloalkyl;
    • V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —N(R19)—, —C(═O)NR19b—, —NR19bC(═O)—, —NR19bS(═O)2—, —S(═O)2NR19b—, —NR19bS(═O)—, —S(═O)NR19b—, —C(═O)O—, or —OC(═O)—;
    • Z is C1-C3 alkyl substituted with 1-2 R12;
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12 is C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • B is a 6, 7, or 8 membered lactam,
      • wherein the lactam is saturated, partially saturated or unsaturated;
      • wherein each additional lactam carbon is substituted with 0-2 R11; and,
      • optionally, the lactam contains a heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)2—, and —N(R10)—;
    • R10 is H, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, S(═O)2R17;
      • C1-C6 alkyl substituted with 0-1 R10a;
      • C6-C10 aryl substituted with 0-4 R10b;
      • C3-C10 carbocycle substituted with 0-3 R10b; or
      • 5 to 10 membered heterocycle optionally substituted with 0-3 R10b;
    • R10a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-4 R10b;
    • R10b, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, or CF3;
    • R11, at each occurrence, is independently selected from
    • C1-C4 alkoxy, Cl, F, Br, I, ═O, CN, NO2, NR18R19, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, CF3;
      • C1-C6 alkyl substituted with 0-1 R11a;
      • C6-C10 aryl substituted with 0-3 R11b;
      • C3-C10 carbocycle substituted with 0-3 R11b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R11b;
    • alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle or a benzo fused radical;
    • R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
    • R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • R14 is H, phenyl, benzyl, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
    • R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl);
    • R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl);
    • R17 is H, aryl, (aryl)CH2—, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
    • R18, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl); and
    • R19, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl); and
    • R19b is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or phenethyl.
  • [0248]
    [3] In a further preferred embodiment the present invention provides
    • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
    • R3 is —(CR7R7a)n—R4,
      • —(CR7R7a)n—S—(CR7R7a) m-R4,
      • —(CR7R7a)n—O—(CR7R7a)m—R4, or
      • —(CR7R7a)n—N(R7b)-(CR7R7a)m—R4;
    • n is 0, 1, or 2;
    • m is 0, 1, or 2;
    • R3a is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, or butoxy;
    • R4 is H, OH, OR14a,
      • C1-C4 alkyl substituted with 0-2 R4a,
      • C2-C4 alkenyl substituted with 0-2 R4a,
      • C2-C4 alkynyl substituted with 0-2 R4a,
      • C3-C6 cycloalkyl substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, or
      • 5 to 10 membered heterocycle substituted with 0-3 R4b;
    • R4a, at each occurrence, is independently selected from is H, F, Cl, Br, I CF3,
      • C3-C10 carbocycle substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, or
      • 5 to 10 membered heterocycle substituted with 0-3 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • R5 is H, OR14;
      • C1-C6 alkyl substituted with 0-3 R5b;
      • C2-C6 alkenyl substituted with 0-3 R5b;
      • C2-C6 alkynyl substituted with 0-3 R5b;
      • C3-C10 carbocycle substituted with 0-3 R5c;
      • C6-C10 aryl substituted with 0-3 R5c; or
      • 5 to 10 membered heterocycle substituted with 0-3R5c;
    • R5a is H, OH, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, or C2-C4 alkenyloxy;
    • R5b, at each occurrence, is independently selected from:
      • H, C1-C6 alkyl, CF3, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16;
      • C3-C10 carbocycle substituted with 0-3 R5c;
      • C6-C10 aryl substituted with 0-3 R5c; or
      • 5 to 10 membered heterocycle substituted with 0-3 R5c;
    • R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • R6 is H, methyl, or ethyl;
    • R7, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, and C1-C4 alkyl;
    • R7a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, phenyl and C1-C4 alkyl;
    • R7b is independently selected from H, methyl, ethyl, propyl, and butyl;
    • W is —(CR8R8a)p—;
    • p is 0, 1, or 2;
    • R8 and R8a, at each occurrence, are independently selected from H, F, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl and C3-C6 cycloalkyl;
    • X is a bond;
      • C6-C10 aryl substituted with 0-3 RXb;
      • C3-C10 carbocycle substituted with 0-2 RXb; or
      • 5 to 10 membered heterocycle substituted with 0-2 RXb;
    • RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • Y is a bond or —(CR9R9a)t—V—(CR9R9a)u—;
    • t is 0, 1, or 2;
    • u is 0, 1, or 2;
    • R9 and R9a, at each occurrence, are independently selected from H, F, C1-C4 alkyl or C3-C6 cycloalkyl;
    • V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —N(R19)—, —C(═O)NR19b—, —NR19bC(═O)—, —NR19bS(═O)2—, —S(═O)2NR19b—, —NR19bS(═O)—, or —S(═O)NR19b—;
    • Z is C1-C3 alkyl substituted with 1-2 R12;
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12 is C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • B is a seven membered lactam,
      • wherein the lactam is saturated, partially saturated or unsaturated;
      • wherein each additional lactam carbon is substituted with 0-2 R11; and,
      • optionally, the lactam contains a heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)2—, and —N(R10)—;
    • R10 is H, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, S(═O)2R17;
      • C1-C6 alkyl substituted with 0-1 R10a;
      • C6-C10 aryl substituted with 0-4 R10b;
      • C3-C10 carbocycle substituted with 0-3 R10b; or
      • 5 to 10 membered heterocycle optionally substituted with 0-3 R10b;
    • R10a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-4 R10b;
    • R10b, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, or CF3;
    • R11, at each occurrence, is independently selected from C1-C4 alkoxy, Cl, F, ═O, NR18R19, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, CF3;
      • C1-C6 alkyl substituted with 0-1 R11a;
      • C6-C10 aryl substituted with 0-3 R11b;
      • C3-C10 carbocycle substituted with 0-3 R11b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R11b;
    • alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle or a benzo fused radical;
    • R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
    • R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • R14 is H, phenyl, benzyl, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
    • R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl);
    • R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl);
    • R17 is H, aryl, (aryl)CH2—, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
    • R18, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl); and
    • R19, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl); and
    • R19b is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or phenethyl.
  • [0334]
    [4] In a further preferred embodiment the present invention provides
    • R3 is —(CR7R7a)n—R4,
      • —(CR7R7a)n—S—(CR7R7a)m—R4,
      • —(CR7R7a)n—O—(CR7R7a)m—R4, or
      • —(CR7R7a)n—N(R7b)—(CR7R7a)m—R4;
    • n is 0 or 1;
    • m is 0 or 1;
    • R3a is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, or butoxy;
    • R4 is H, OH,
      • C1-C4 alkyl substituted with 0-2 R4a,
      • C2-C4 alkenyl substituted with 0-2 R4a,
      • C2-C4 alkynyl substituted with 0-1 R4a,
      • C3-C6 cycloalkyl substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, or
      • 5 to 10 membered heterocycle substituted with 0-3 R4b;
    • R4a, at each occurrence, is independently selected from is H, F, Cl, CF3,
      • C3-C6 cycloalkyl substituted with 0-3 R4b, phenyl substituted with 0-3 R4b, or
      • 5 to 6 membered heterocycle substituted with 0-3 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • R5 is H, OR14;
      • C1-C4 alkyl substituted with 0-3 R5b;
      • C2-C4 alkenyl substituted with 0-2 R5b; or
      • C2-C4 alkynyl substituted with 0-2 R5b;
    • R5a is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, or allyl;
    • R5b, at each occurrence, is independently selected from:
      • H, methyl, ethyl, propyl, butyl, CF3, OR14, ═O;
      • C3-C6 cycloalkyl substituted with 0-2 R5c;
      • phenyl substituted with 0-3 R5c; or
      • 5 to 6 membered heterocycle substituted with 0-2 R5c;
    • R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • R6 is H;
    • R7, at each occurrence, is independently selected from H, F, CF3, methyl, and ethyl;
    • R7a, at each occurrence, is independently selected from H, F, CF3, methyl, and ethyl;
    • R7b is independently selected from H, methyl, and ethyl;
    • W is a bond, —CH2—, —CH(CH3)—, —CH2CH2— or —CH(CH3)CH2—;
    • X is a bond;
      • phenyl substituted with 0-2 RXb;
      • C3-C6 cycloalkyl substituted with 0-2 RXb; or
      • 5 to 6 membered heterocycle substituted with 0-2 RXb;
    • RXb, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • Y is a bond, —CH2—V—, —V—, or —V—CH2—;
    • V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(CH3)—, or —N(CH2CH3)—,
    • Z is C1-C2 alkyl substituted with 1-2 R12;
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C6 carbocycle substituted with 0-3 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12 is C6-C10 aryl substituted with 0-4 R12b;
      • C3-C6 carbocycle substituted with 0-3 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • B is a seven membered lactam,
      • wherein the lactam is saturated, partially saturated or unsaturated;
      • wherein each additional lactam carbon is substituted with 0-2 R11; and,
      • optionally, the lactam contains a heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)2—, and —N(R10)—;
    • R10 is H, C(═O)R17, C(═O)OR17;
      • C1-C4 alkyl substituted with 0-1 R10a;
      • phenyl substituted with 0-4 R10b;
      • C3-C6 carbocycle substituted with 0-3 R10b; or
      • 5 to 6 membered heterocycle optionally substituted with 0-3 R10b;
    • R10a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-4 R10b;
    • R10b, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, C1-C3 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, or CF3;
    • R11, at each occurrence, is independently selected from
      • C1-C4 alkoxy, Cl, F, ═O, NR18R19, C(═O)R17, C(═O)OR17, CF3;
      • C1-C4 alkyl substituted with 0-1 R11a;
      • phenyl substituted with 0-3 R11b;
      • C3-C6 carbocycle substituted with 0-3 R11b; or
      • 5 to 6 membered heterocycle substituted with 0-3 R11b;
    • alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a benzo fused radical;
    • R11a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, F, ═O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
    • R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • R14 is H, phenyl, benzyl, C1-C4 alkyl, or C2-C4 alkoxyalkyl;
    • R15, at each occurrence, is independently selected from H, C1-C4 alkyl, benzyl, phenethyl, —C(═O)—(C1-C4 alkyl) and —S(═O)2—(C1-C4 alkyl);
    • R16, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, benzyl, phenethyl, —C(═O)—(C1-C4 alkyl) and —S(═O)2—(C1-C4 alkyl);
    • R17 is H, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl, (4-methylphenyl)methyl, (4-trifluorophenyl)methyl, methyl, ethyl, propyl, butyl, methoxymethyl, methyoxyethyl, ethoxymethyl, or ethoxyethyl;
    • R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
    • R19, at each occurrence, is independently selected from H, methyl, and ethyl.
  • [0410]
    [5] In a more preferred embodiment the present invention provides
    • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
    • R3 is —CH3, —CH2CH3, —CH2CH2CH3, —CH2CH2CH2CH3, —CH2 (CH3)2, —CH(CH3)CH2CH3, —CH2CH(CH3)2, —CH2C(CH3)3, —CF3, —CH2CF3, —CH2CH2CF3, —CH2CH2CH2CF3,
      • —CH═CH2, —CH2CH═CH2, —CH2C(CH3)═CH2, —CH2CH═C(CH3)2, —CH2CH2CH═CH2, —CH2CH2C(CH3)═CH2, —CH2CH2CH═C(CH3)2, cis-CH2CH═CH(CH3), cis-CH2CH2CH═CH(CH3), trans-CH2CH═CH(CH3), trans-CH2CH2CH═CH(CH3);
      • —C≡CH, —CH2C═CH, —CH2C≡C(CH3),
      • cyclopropyl-CH2—, cyclobutyl-CH2—, cyclopentyl-CH2—, cyclohexyl-CH2—, cyclopropyl-CH2CH2—, cyclobutyl-CH2CH2—, cyclopentyl-CH2CH2—, cyclohexyl-CH2CH2—,
      • phenyl-CH2—,
      • (2-F-phenyl)CH2—, (3-F-phenyl)CH2—, (4-F-phenyl)CH2—, (2-Cl-phenyl)CH2—, (3-Cl-phenyl)CH2—, (4-Cl-phenyl)CH2—,
      • (2,3-diF-phenyl)CH2—, (2,4-diF-phenyl)CH2—,
      • (2,5-diF-phenyl)CH2—, (2,6-diF-phenyl)CH2—,
      • (3,4-diF-phenyl)CH2—, (3,5-diF-phenyl)CH2—,
      • (2,3-diCl-phenyl)CH2—, (2,4-diCl-phenyl)CH2—,
      • (2,5-diCl-phenyl)CH2—, (2,6-diCl-phenyl)CH2—,
      • (3,4-diCl-phenyl)CH2—, (3,5-diCl-phenyl)CH2—,
      • (3-F-4-Cl-phenyl)CH2—, (3-F-5-Cl-phenyl)CH2—,
      • (3-Cl-4-F-phenyl)CH2—,
      • phenyl-CH2CH2—,
      • (2-F-phenyl)CH2CH2—, (3-F-phenyl)CH2CH2—,
      • (4-F-phenyl)CH2CH2—, (2-Cl-phenyl)CH2CH2—,
      • (3-Cl-phenyl)CH2CH2—, (4-Cl-phenyl)CH2CH2—,
      • (2,3-diF-phenyl)CH2CH2—, (2,4-diF-phenyl)CH2CH2—,
      • (2,5-diF-phenyl)CH2CH2—, (2,6-diF-phenyl)CH2CH2—,
      • (3,4-diF-phenyl)CH2CH2—, (3,5-diF-phenyl)CH2CH2—,
      • (2,3-diCl-phenyl)CH2CH2—, (2,4-diCl-phenyl)CH2CH2—,
      • (2,5-diCl-phenyl)CH2CH2—, (2,6-diCl-phenyl)CH2CH2—,
      • (3,4-diCl-phenyl)CH2CH2—, (3,5-diCl-phenyl)CH2CH2—,
      • (3-F-4-Cl-phenyl)CH2CH2—, (3-F-5-Cl-phenyl)CH2CH2—, or
    • R5 is —CH3, —CH2CH3, —CH2CH2CH3, —CH2(CH3)2, —CH2CH2CH2CH3, —CH(CH3)CH2CH3, —CH2CH(CH3)2, —CH2C(CH3)3, —CH2CH2CH2CH2CH3, —CH(CH3)CH2CH2CH3, —CH2CH(CH3)CH2CH3, —CH2CH2CH(CH3)2, —CH(CH2CH3)2, —CF3, —CH2CF3, —CH2CH2CF3, —CH2CH2CH2CF3, —CH2CH2CH2CH2CF3, —CH═CH2, —CH2CH═CH2, —CH═CHCH3, cis-CH2CH═CH(CH3), trans-CH2CH═CH(CH3), trans-CH2CH═CH(C6H5), —CH2CH═C(CH3)2, cis-CH2CH═CHCH2CH3, trans-CH2CH═CHCH2CH3, cis-CH2CH2CH═CH(CH3), trans-CH2CH2CH═CH(CH3), trans-CH2CH═CHCH2(C6H5), —C≡CH, —CH2C≡CH, —CH2C≡C(CH3), —CH2C≡C(C6H5) —CH2CH2C≡CH, —CH2CH2C≡C(CH3), —CH2CH2C≡C(C6H5) —CH2CH2CH2C≡CH, —CH2CH2CH2CC(CH3), —CH2CH2CH2C(C6H5)
      • cyclopropyl-CH2—, cyclobutyl-CH2—, cyclopentyl-CH2—, cyclohexyl-CH2—, (2-CH3-cyclopropyl)CH2—, (3-CH3-cyclobutyl) CH2—, cyclopropyl-CH2CH2—, cyclobutyl-CH2CH2—, cyclopentyl-CH2CH2—, cyclohexyl-CH2CH2—, (2-CH3-cyclopropyl)CH2CH2—, (3-CH3-cyclobutyl)CH2CH2—,
      • phenyl-CH2—, (2-F-phenyl)CH2—, (3-F-phenyl)CH2—,
      • (4-F-phenyl)CH2—, furanyl-CH2—, thienyl-CH2—, pyridyl-CH2—, 1-imidazolyl-CH2—, oxazolyl-CH2—, isoxazolyl-CH2—,
      • phenyl-CH2CH2—, (2-F-phenyl)CH2CH2—, (3-F-phenyl)CH2CH2—,
      • (4-F-phenyl)CH2CH2—, furanyl-CH2CH2—, thienyl-CH2CH2—, pyridyl-CH2CH2—, 1-imidazolyl-CH2CH2—, oxazolyl-CH2CH2—,
      • isoxazolyl-CH2CH2—,
    • W is a bond, —CH2—, or —CH(CH3)—;
    • X is a bond;
    • Y is a bond, —CH2—V—, —V—, or —V—CH2—;
    • V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, or —N(CH3)—,
    • Z is phenyl 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-4-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF3O-phenyl, 3-CF3O-phenyl, 4-CF3O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholino, N-piperinyl, phenyl-CH2—, (2-F-phenyl)CH2—, (3-F-phenyl)CH2—, (4-F-phenyl)CH2—, (2-Cl-phenyl)CH2—, (3-Cl-phenyl)CH2—, (4-Cl-phenyl)CH2—, (2,3-diF-phenyl)CH2—, (2,4-diF-phenyl)CH2—, (2,5-diF-phenyl)CH2—, (2,6-diF-phenyl)CH2—, (3,4-diF-phenyl)CH2—, (3,5-diF-phenyl)CH2—, (2,3-diCl-phenyl)CH2—, (2,4-diCl-phenyl)CH2—, (2,5-diCl-phenyl)CH2—, (2,6-diCl-phenyl)CH2—, (3,4-diCl-phenyl)CH2—, (3,5-diCl-phenyl)CH2—, (3-F-4-Cl-phenyl)CH2—, (3-F-5-Cl-phenyl)CH2—, (3-Cl-4-F-phenyl)CH2—, (2-MeO-phenyl)CH2—, (3-MeO-phenyl)CH2—, (4-MeO-phenyl)CH2—, (2-Me-phenyl)CH2—, (3-Me-phenyl)CH2—, (4-Me-phenyl)CH2—, (2-MeS-phenyl)CH2—, (3-MeS-phenyl)CH2—, 4-MeS-phenyl)CH2—, (2-CF3O-phenyl)CH2—, (3-CF3O-phenyl)CH2—, (4-CF3O-phenyl)CH2—, (furanyl)CH2—, (thienyl)CH2—, (pyridyl)CH2—, (2-Me-pyridyl)CH2—, (3-Me-pyridyl)CH2—, (4-Me-pyridyl)CH2—, (1-imidazolyl)CH2—, (oxazolyl)CH2—, (isoxazolyl)CH2—, (1-benzimidazolyl)CH2—, (cyclopropyl)CH2—, (cyclobutyl)CH2—, (cyclopentyl)CH2—, (cyclohexyl)CH2—, (morpholino)CH2—, (N-pipridinyl)CH2—, phenyl-CH2CH2—, (phenyl)2CHCH2—, (2-F-phenyl)CH2CH2—, (3-F-phenyl)CH2CH2—, (4-F-phenyl)CH2CH2—, (2-Cl-phenyl)CH2CH2—, (3-Cl-phenyl)CH2CH2—, (4-Cl-phenyl)CH2CH2—, (2,3-diF-phenyl)CH2CH2—, (2,4-diF-phenyl)CH2CH2—, (2,5-diF-phenyl)CH2CH2—, (2,6-diF-phenyl)CH2CH2—, (3,4-diF-phenyl)CH2CH2—, (3,5-diF-phenyl)CH2CH2—, (2,3-diCl-phenyl)CH2CH2—, (2,4-diCl-phenyl)CH2CH2—, (2,5-diCl-phenyl)CH2CH2—, (2,6-diCl-phenyl)CH2CH2—, (3,4-diCl-phenyl)CH2CH2—, (3,5-diCl-phenyl)CH2CH2—, (3-F-4-Cl-phenyl)CH2CH2—, (3-F-5-Cl-phenyl)CH2CH2—, (3-Cl-4-F-phenyl)CH2CH2—, (2-MeO-phenyl)CH2CH2—, (3-MeO-phenyl)CH2CH2—, (4-MeO-phenyl)CH2CH2—, (2-Me-phenyl)CH2CH2—, (3-Me-phenyl)CH2CH2—, (4-Me-phenyl)CH2CH2—, (2-MeS-phenyl)CH2CH2—, (3-MeS-phenyl)CH2CH2—, (4-MeS-phenyl)CH2CH2—, (2-CF3O-phenyl)CH2CH2—, (3-CF3O-phenyl)CH2CH2—, (4-CF3O-phenyl)CH2CH2—, (furanyl)CH2CH2—, (thienyl)CH2CH2—, (pyridyl)CH2CH2—, (2-Me-pyridyl)CH2CH2—, (3-Me-pyridyl)CH2CH2—, (4-Me-pyridyl)CH2CH2—, (imidazolyl)CH2CH2—, (oxazolyl)CH2CH2—, (isoxazolyl)CH2CH2—, (benzimidazolyl)CH2CH2—, (cyclopropyl)CH2CH2—, (cyclobutyl)CH2CH2—, (cyclopentyl)CH2CH2—, (cyclohexyl)CH2CH2—, (morpholino)CH2CH2—, (N-pipridinyl)CH2CH2—,
    • B is a seven membered lactam,
      • wherein the lactam is saturated, partially saturated or unsaturated;
      • wherein each additional lactam carbon is substituted with 0-2 R11; and,
      • optionally, the lactam contains a heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)2—, and —N(R10)—;
    • R10 is H, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH2—, (4-F-phenyl)CH2CH2—, 4-Cl-phenyl, (4-Cl-phenyl)CH2—, (4-Cl-phenyl)CH2CH2—, 4-CH3-phenyl, (4-CH3-phenyl)CH2—, (4-CH3-phenyl)CH2CH2—, 4-CF3-phenyl, (4-CF3-phenyl)CH2—, or (4-CF3-phenyl) CH2CH2—;
    • R11, at each occurrence, is independently selected from H, ═O, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH2—, (4-F-phenyl)CH2CH2—, 4-Cl-phenyl, (4-Cl-phenyl)CH2—, (4-Cl-phenyl)CH2CH2—, 4-CH3-phenyl, (4-CH3-phenyl)CH2—, (4-CH3-phenyl)CH2CH2—, 4-CF3-phenyl, (4-CF3-phenyl)CH2—, or (4-CF3-phenyl) CH2CH2—; and
    • alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a benzo fused radical.
  • [0456]
    [6] In a futher more preferred embodiment the present invention provides
    • B is
  • [0458]
    [7] In an even more preferred embodiment the present invention provides
    • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
    • R3 is R4,
    • R4 is C1-C4 alkyl substituted with 0-2 R4a,
      • C2-C4 alkenyl substituted with 0-2 R4a,
      • C2-C4 alkynyl substituted with 0-2 R4a,
    • R4a, at each occurrence, is independently selected from is H, F, CF3,
      • C3-C6 cycloalkyl substituted with 0-3 R4b,
      • phenyl substituted with 0-3 R4b, or
      • 5 to 6 membered heterocycle substituted with 0-3 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • R5 is C1-C4 alkyl substituted with 0-3 R5b;
      • C2-C4 alkenyl substituted with 0-2 R5b; or
      • C2-C4 alkynyl substituted with 0-2 R5b;
    • R5b, at each occurrence, is independently selected from:
      • H, methyl, ethyl, propyl, butyl, CF3, OR14, ═O;
      • C3-C6 cycloalkyl substituted with 0-2 R5c;
      • phenyl substituted with 0-3 R5c; or
      • 5 to 6 membered heterocycle substituted with 0-2 R5c;
    • R5c, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • W is —CH2—, or —CH(CH3)—;
    • X is a bond;
      • phenyl substituted with 0-2 RXb;
      • C3-C6 cycloalkyl substituted with 0-2 RXb; or
      • 5 to 6 membered heterocycle substituted with 0-2 RXb;
    • RXb, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • Y is a bond, —CH2—V—, —V—, or —V—CH2—;
    • V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(CH3)—, or —N(CH2CH3)—,
    • Z is C1-C2 alkyl substituted with 1-2 R12;
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C6 carbocycle substituted with 0-3 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12 is C6-C10 aryl substituted with 0-4 R12b;
      • C3-C6 carbocycle substituted with 0-3 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • R11 is methoxy, ethoxy, propoxy, butoxy, Cl, F, ═O, NR18R19, CF3;
      • C1-C4 alkyl substituted with 0-1 R11a;
      • phenyl substituted with 0-3 R11b;
      • C3-C6 carbocycle substituted with 0-3 R11b; or
      • 5 to 6 membered heterocycle substituted with 0-3 R11b;
    • alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a benzo fused radical;
    • R11a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, F, ═O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
    • R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • R14 is H, phenyl, benzyl, methyl, ethyl, propyl, butyl;
    • R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
    • R16, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, benzyl, phenethyl, —C(═O)—(C1-C4 alkyl) and —S(═O)2—(C1-C4 alkyl);
    • R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
    • R19, at each occurrence, is independently selected from H, methyl, and ethyl.
  • [0507]
    [8] In another even more preferred embodiment the present invention provides
    • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
    • R3 is R4,
    • R4 is C1-C4 alkyl substituted with 0-2 R4a,
      • C2-C4 alkenyl substituted with 0-2 R4a,
      • C2-C4 alkynyl substituted with 0-2 R4a,
    • R4a, at each occurrence, is independently selected from is H, F, CF3,
      • C3-C6 cycloalkyl substituted with 0-3 R4b, phenyl substituted with 0-3 R4b, or
      • 5 to 6 membered heterocycle substituted with 0-3 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • R5 is C1-C4 alkyl substituted with 0-3 R5b;
      • C2-C4 alkenyl substituted with 0-2 R5b; or
      • C2-C4 alkynyl substituted with 0-2 R5b;
    • R5b, at each occurrence, is independently selected from:
      • H, methyl, ethyl, propyl, butyl, CF3, OR14, ═O;
      • C3-C6 cycloalkyl substituted with 0-2 R5c;
      • phenyl substituted with 0-3 R5c; or
      • 5 to 6 membered heterocycle substituted with 0-2 R5c;
    • R5c, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • W is —CH2—, or —CH(CH3)—;
    • X is a bond;
      • phenyl substituted with 0-2 RXb;
      • C3-C6 cycloalkyl substituted with 0-2 RXb; or
      • 5 to 6 membered heterocycle substituted with 0-2 RXb;
    • RXb, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • Y is a bond, —CH2—V—, —V—, or —V—CH2—;
    • V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(CH3)—, or —N(CH2CH3)—,
    • Z is C1-C2 alkyl substituted with 1-2 R12;
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C6 carbocycle substituted with 0-3 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12 is C6-C10 aryl substituted with 0-4 R12b;
      • C3-C6 carbocycle substituted with 0-3 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • R10 is H, C(═O)R17, C(═O)OR17;
      • C1-C4 alkyl substituted with 0-1 R10a;
      • phenyl substituted with 0-4 R10b;
      • C3-C6 carbocycle substituted with 0-3 R10b; or
      • 5 to 6 membered heterocycle optionally substituted with 0-3 R10b;
    • R10a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-4 R10b;
    • R10b, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, Br, I, CN, NO2, NR15R16, or CF3;
    • R14 is H, phenyl, benzyl, methyl, ethyl, propyl, butyl;
    • R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
    • R16, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, benzyl, phenethyl, —C(═O)—(C1-C4 alkyl) and —S(═O)2—(C1-C4 alkyl); and
    • R17 is H, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl, (4-methylphenyl)methyl, (4-trifluorophenyl)methyl, methyl, ethyl, propyl, butyl, methoxymethyl, methyoxyethyl, ethoxymethyl, or ethoxyethyl.
  • [0553]
    [9] In another even more preferred embodiment the present invention provides
    • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
    • R3 is R4,
    • R4 is C1-C4 alkyl substituted with 0-2 R4a,
      • C2-C4 alkenyl substituted with 0-2 R4a,
      • C2-C4 alkynyl substituted with 0-2 R4a,
    • R4a, at each occurrence, is independently selected from is H, F, CF3,
      • C3-C6 cycloalkyl substituted with 0-3 R4b,
      • phenyl substituted with 0-3 R4b, or
      • 5 to 6 membered heterocycle substituted with 0-3 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • R5 is C1-C4 alkyl substituted with 0-3 R5b;
      • C2-C4 alkenyl substituted with 0-2 R5b; or
      • C2-C4 alkynyl substituted with 0-2 R5b;
    • R5b, at each occurrence, is independently selected from:
      • H, methyl, ethyl, propyl, butyl, CF3, OR14, ═O;
      • C3-C6 cycloalkyl substituted with 0-2 R5C;
      • phenyl substituted with 0-3 R5c; or
      • 5 to 6 membered heterocycle substituted with 0-2 R5c;
    • R5c, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • W is —CH2—, or —CH(CH3)—;
    • X is a bond;
      • phenyl substituted with 0-2 RXb;
      • C3-C6 cycloalkyl substituted with 0-2 RXb; or
      • 5 to 6 membered heterocycle substituted with 0-2 RXb;
    • RXb, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • Y is a bond, —CH2—V—, —V—, or —V—CH2—;
    • V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(CH3)—, or —N(CH2CH3)—,
    • Z is C1-C2 alkyl substituted with 1-2 R12;
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C6 carbocycle substituted with 0-3 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12 is C6-C10 aryl substituted with 0-4 R12b;
      • C3-C6 carbocycle substituted with 0-3 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • R11 is methoxy, ethoxy, propoxy, butoxy, Cl, F, ═O, NR18R19, CF3;
      • C1-C4 alkyl substituted with 0-1 R11a;
      • phenyl substituted with 0-3 R11b;
      • C3-C6 carbocycle substituted with 0-3 R11b; or
      • 5 to 6 membered heterocycle substituted with 0-3 R11b;
    • R11a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, F, ═O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
    • R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • R14 is H, phenyl, benzyl, methyl, ethyl, propyl, butyl;
    • R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
    • R16, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, benzyl, phenethyl, —C(═O)—(C1-C4 alkyl) and —S(═O)2—(C1-C4 alkyl);
    • R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
    • R19, at each occurrence, is independently selected from H, methyl, and ethyl.
  • [0601]
    [10] In another even more preferred embodiment the present invention provides
    • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
    • R3 is R4,
    • R4 is C1-C4 alkyl substituted with 0-2 R4a,
      • C2-C4 alkenyl substituted with 0-2 R4a,
      • C2-C4 alkynyl substituted with 0-1 R4a,
    • R4a, at each occurrence, is independently selected from is H, F, CF3,
      • C3-C6 cycloalkyl substituted with 0-3 R4b,
      • phenyl substituted with 0-3 R4b, or
      • 5 to 6 membered heterocycle substituted with 0-3 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • R5 is C1-C4 alkyl substituted with 0-3 R5b;
      • C2-C4 alkenyl substituted with 0-2 R5b; or
      • C2-C4 alkynyl substituted with 0-2 R5b;
    • R5b, at each occurrence, is independently selected from:
      • H, methyl, ethyl, propyl, butyl, CF3, OR14, ═O;
      • C3-C6 cycloalkyl substituted with 0-2 R5c;
      • phenyl substituted with 0-3 R5c; or
      • 5 to 6 membered heterocycle substituted with 0-2 R5c;
    • R5c, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • W is —CH2—, or —CH(CH3)—;
    • X is a bond;
      • phenyl substituted with 0-2 RXb;
      • C3-C6 cycloalkyl substituted with 0-2 RXb; or
      • 5 to 6 membered heterocycle substituted with 0-2 RXb;
    • RXb, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • Y is a bond, —CH2—V—, —V—, or —V—CH2—;
    • V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(CH3)—, or —N(CH2CH3)—,
    • Z is C1-C2 alkyl substituted with 1-2 R12;
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C6 carbocycle substituted with 0-3 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12 is C6-C10 aryl substituted with 0-4 R12b;
      • C3-C6 carbocycle substituted with 0-3 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • R14 is. H, phenyl, benzyl, methyl, ethyl, propyl, butyl;
    • R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; and
    • R16, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, benzyl, phenethyl, —C(═O)—(C1-C4 alkyl) and —S(═O)2—(C1-C4 alkyl).
  • [0640]
    [11] In another preferred embodiment the present invention provides
    • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
    • R3 is —(CR7R7a)n—R4,
      • —(CR7R7a)n—S—(CR7R7a)m—R4,
      • —(CR7R7a)n—O—(CR7R7a)m—R4, or
      • —(CR7R7a)n—N(R7b)—(CR7R7a)m—R4;
    • n is 0, 1, or 2;
    • m is 0, 1, or 2;
    • R3a is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, or butoxy;
    • R4 is H, OH, OR14a,
      • C1-C4 alkyl substituted with 0-2 R4a,
      • C2-C4 alkenyl substituted with 0-2 R4a,
      • C2-C4 alkynyl substituted with 0-2 R4a,
      • C3-C6 cycloalkyl substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, or
      • 5 to 10 membered heterocycle substituted with 0-3 R4b;
    • R4a, at each occurrence, is independently selected from is H, F, Cl, Br, I CF3,
      • C3-C10 carbocycle substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, or
      • 5 to 10 membered heterocycle substituted with 0-3 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • R5 is H, OR14;
      • C1-C6 alkyl substituted with 0-3 R5b;
      • C2-C6 alkenyl substituted with 0-3 R5b;
      • C2-C6 alkynyl substituted with 0-3 R5b;
      • C3-C10 carbocycle substituted with 0-3 R5c;
      • C6-C10 aryl substituted with 0-3 R5c; or
      • 5 to 10 membered heterocycle substituted with 0-3R5c;
    • R5a is H, OH, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, or C2-C4 alkenyloxy;
    • R5b, at each occurrence, is independently selected from:
      • H, C1-C6 alkyl, CF3, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16;
      • C3-C10 carbocycle substituted with 0-3 R5c;
      • C6-C10 aryl substituted with 0-3 R5c; or
      • 5 to 10 membered heterocycle substituted with 0-3 R5c;
    • R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • R6 is H, methyl, or ethyl;
    • R7, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, and C1-C4 alkyl;
    • R7a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, phenyl and C1-C4 alkyl;
    • R7b is independently selected from H, methyl, ethyl, propyl, and butyl;
    • W is —(CR8R8a)p—;
    • p is 0, 1, or 2;
    • R8 and R8a, at each occurrence, are independently selected from H, F, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl and C3-C6 cycloalkyl;
    • X is a bond;
      • C6-C10 aryl substituted with 0-3 RXb;
      • C3-C10 carbocycle substituted with 0-2 RXb; or
      • 5 to 10 membered heterocycle substituted with 0-2 RXb;
    • RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • Y is a bond or —(CR9R9a)t—V—(CR9R9a)u—;
    • t is 0, 1, or 2;
    • u is 0, 1, or 2;
    • R9 and R9a, at each occurrence, are independently selected from H, F, C1-C4 alkyl or C3-C6 cycloalkyl;
    • V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —N(R19)—C(═O)NR19b—, —NR19bC(═O)—, —NR19bS(═O)2—, —S(═O)2NR19b—, —NR19bS(═O)—, or —S(═O)NR19b—;
    • Z is C1-C3 alkyl substituted with 1-2 R12;
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12 is C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • B is a seven membered lactam,
      • wherein the lactam is saturated, partially saturated or unsaturated;
      • wherein each additional lactam carbon is substituted with 0-2 R11; and,
      • optionally, the lactam contains a heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)2—, and —N(R10)—;
    • R10 is H, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, S(═O)2R17;
      • C1-C6 alkyl substituted with 0-1 R10a;
      • C6-C10 aryl substituted with 0-4 R10b;
      • C3-C10 carbocycle substituted with 0-3 R10b; or
      • 5 to 10 membered heterocycle optionally substituted with 0-3 R10b;
    • R10a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-4 R10b;
    • R10b, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, or CF3;
    • R11, at each occurrence, is independently selected from
      • C1-C4 alkoxy, Cl, F, ═O, NR18R19, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, CF3;
      • C1-C6 alkyl substituted with 0-1 R11a;
      • C6-C10 aryl substituted with 0-3 R11b;
      • C3-C10 carbocycle substituted with 0-3 R11b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R11b;
    • alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle or a benzo fused radical;
    • R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
    • R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • R14 is H, phenyl, benzyl, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
    • R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl);
    • R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl);
    • R17 is H, aryl, (aryl)CH2—, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
    • R18, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl); and
    • R19, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl); and
    • R19b is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or phenethyl.
  • [0727]
    [12] In a more preferred embodiment the present invention provides
    • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
    • R3 is R4,
    • n is 0 or 1;
    • m is 0 or 1;
    • R4 is H, OH,
      • C1-C4 alkyl substituted with 0-2 R4a,
      • C2-C4 alkenyl substituted with 0-2 R4a,
      • C2-C4 alkynyl substituted with 0-1 R4a,
      • C3-C6 cycloalkyl substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, or
      • 5 to 10 membered heterocycle substituted with 0-3 R4b;
    • R4a, at each occurrence, is independently selected from is H, F, Cl, CF3,
      • C3-C6 cycloalkyl substituted with 0-3 R4b,
      • phenyl substituted with 0-3 R4b, or
      • 5 to 6 membered heterocycle substituted with 0-3 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • R5 is H, OR14;
      • C1-C4 alkyl substituted with 0-3 R5b;
      • C2-C4 alkenyl substituted with 0-2 R5b; or
      • C2-C4 alkynyl substituted with 0-2 R5b;
    • R5b, at each occurrence, is independently selected from:
      • H, methyl, ethyl, propyl, butyl, CF3, OR14, ═O;
      • C3-C6 cycloalkyl substituted with 0-2 R5c;
      • phenyl substituted with 0-3 R5c; or
      • 5 to 6 membered heterocycle substituted with 0-2 R5c;
    • R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • W is a bond, —CH2—, —CH(CH3)—, —CH2CH2— or —CH(CH3)CH2—;
    • X is a bond;
      • phenyl substituted with 0-2 RXb;
      • C3-C6 cycloalkyl substituted with 0-2 RXb; or
      • 5 to 6 membered heterocycle substituted with 0-2 RXb;
    • RXb, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • Y is a bond, —CH2—V—, —V—, or —V—CH2—;
    • V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(CH3)—, or —N(CH2CH3)—,
    • Z is C1-C2 alkyl substituted with 1-2 R12;
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C6 carbocycle substituted with 0-3 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12 is C6-C10 aryl substituted with 0-4 R12b;
      • C3-C6 carbocycle substituted with 0-3 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • B is a seven membered lactam,
      • wherein the lactam is saturated, partially saturated or unsaturated;
      • wherein each additional lactam carbon is substituted with 0-2 R11; and,
      • optionally, the lactam contains a heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)2—, and —N(R10)—;
    • R10 is H, C(═O)R17, C(═O)OR17;
      • C1-C4 alkyl substituted with 0-1 R10a;
      • phenyl substituted with 0-4 R10b;
      • C3-C6 carbocycle substituted with 0-3 R10b; or
      • 5 to 6 membered heterocycle optionally substituted with 0-3 R10b;
    • R10a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-4 R10b;
    • R10b, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, C1-C3 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, or CF3;
    • R11, at each occurrence, is independently selected from
      • C1-C4 alkoxy, Cl, F, ═O, NR18R19, C(═O)R17, C(═O)OR17, CF3;
      • C1-C4 alkyl substituted with 0-1 R11a;
      • phenyl substituted with 0-3 R11b;
      • C3-C6 carbocycle substituted with 0-3 R11b; or
      • 5 to 6 membered heterocycle substituted with 0-3 R11b;
    • alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a benzo fused radical;
    • R11a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, F, ═O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
    • R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • R14 is H, phenyl, benzyl, C1-C4 alkyl, or C2-C4 alkoxyalkyl;
    • R15, at each occurrence, is independently selected from H, C1-C4 alkyl, benzyl, phenethyl, —C(═O)—(C1-C4 alkyl) and —S(═O)2—(C1-C4 alkyl);
    • R16, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, benzyl, phenethyl, —C(═O)—(C1-C4 alkyl) and —S(═O)2—(C1-C4 alkyl);
    • R17 is H, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl, (4-methylphenyl)methyl, (4-trifluorophenyl)methyl, methyl, ethyl, propyl, butyl, methoxymethyl, methyoxyethyl, ethoxymethyl, or ethoxyethyl;
    • R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
    • R19, at each occurrence, is independently selected from H, methyl, and ethyl.
  • [0796]
    [13] In an even more preferred embodiment the present invention provides
    • B is
  • [0798]
    [14] In a preferred embodiment the present provides
    • A is S;
    • Q is —NR1R2;
    • R1, at each occurrence, is independently selected from:
      • H;
      • C1-C6 alkyl substituted with 0-3 R1a;
      • C2-C6 alkenyl substituted with 0-3 R1a;
    • R1a, at each occurrence, is independently selected from H, OR14, F, ═O, NR15R16, CF3;
      • C3-C6 cycloalkyl substituted with 0-3 R1b;
      • phenyl substituted with 0-3 R1b; and
      • 5 to 6 membered heterocycle substituted with 0-3 R1b;
    • R1b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • R2 is independently selected from H, NH2, OH, C1-C6 alkyl, C1-C6 alkoxy, phenoxy, and benzyloxy;
    • R3 is —(CR7R7a)n—R4,
      • —(CR7R7a)n—S—(CR7R7a)m—R4,
      • —(CR7R7a)n—O—(CR7R7a)m—R4,
      • —(CR7R7a)n—N(R7b)—(CR7R7a) m-R4,
      • —(CR7R7a)n—S(═O)—(CR7R7a)m—R4,
      • —(CR7R7a)n—S(═O)2—(CR7R7a)m—R4,
      • —(CR7R7a)n—C(═O)—(CR7R7a)m—R4,
      • —(CR7R7a)n—NHC(═O)—(CR7R7a)m—R4,
      • —(CR7R7a)n—C(═O)NH—(CR7R7a)m—R4,
      • —(CR7R7a)n—NHS(═O)2—(CR7R7a)m—R4, or
      • —(CR7R7a)n—S(═O)2NH—(CR7R7a)m—R4;
    • n is 0, 1, 2, or 3;
    • m is 0, 1, 2, or 3;
    • R3a is H, OH, C1-C4 alkyl, C1-C4 alkoxy, or C2-C4 alkenyloxy;
    • R4 is H, OH, OR14a,
      • C1-C6 alkyl substituted with 0-3 R4a,
      • C2-C6 alkenyl substituted with 0-3 R4a,
      • C2-C6 alkynyl substituted with 0-3 R4a,
      • C3-C10 carbocycle substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, or
      • 5 to 10 membered heterocycle substituted with 0-3 R4b;
    • R4a, at each occurrence, is independently selected from is H, F, Cl, Br, I, CF3,
      • C3-C10 carbocycle substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, or
      • 5 to 10 membered heterocycle substituted with 0-3 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • R5 is H, OR14;
      • C1-C6 alkyl substituted with 0-3 R5b;
      • C1-C6 alkoxy substituted with 0-3 R5b;
      • C2-C6 alkenyl substituted with 0-3 R5b;
      • C2-C6 alkynyl substituted with 0-3 R5b;
      • C3-C10 carbocycle substituted with 0-3 R5c;
      • C6-C10 aryl substituted with 0-3 R5c; or
      • 5 to 10 membered heterocycle substituted with 0-3R5c;
    • R5a is H, OH, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, or C2-C4 alkenyloxy;
    • R5b, at each occurrence, is independently selected from:
      • H, C1-C6 alkyl, CF3, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16;
      • C3-C10 carbocycle substituted with 0-3 R5c;
      • C6-C10 aryl substituted with 0-3 R5c; or
      • 5 to 10 membered heterocycle substituted with 0-3 R5c;
    • R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • R6 is H;
      • C1-C6 alkyl substituted with 0-3 R6a;
      • C3-C6 carbocycle substituted with 0-3 R6b; or
      • C6-C10 aryl substituted with 0-3R6b;
    • R6a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, phenyl or CF3;
    • R6b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • R7, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, and C1-C4 alkyl;
    • R7a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, aryl and C1-C4 alkyl;
    • R7b is independently selected from H and C1-C4 alkyl;
    • W is (CR8R8a)p—;
    • p is 0, 1, 2, 3, or 4;
    • R8 and R8a, at each occurrence, are independently selected from H, F, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and C3-C8 cycloalkyl;
    • X is a bond;
      • C6-C10 aryl substituted with 0-3 RXb;
      • C3-C10 carbocycle substituted with 0-3 RXb; or
      • 5 to 10 membered heterocycle substituted with 0-2 RXb;
    • RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • Y is a bond or —(CR9R9a)t—V—(CR9R9a)u—;
    • t is 0, 1, 2, or 3;
    • u is 0, 1, 2, or 3;
    • R9 and R9a, at each occurrence, are independently selected from H, F, C1-C6 alkyl or C3-C8 cycloalkyl;
    • V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —N(R19)—, —C(═O)NR19b—, —NR19bC(═O)—, —NR19bS(═O)2—, —S(═O)2NR19b—, —NR19bS(═O)—, —S(═O)NR19b—, —C(═O)O—, or —OC(═O)—;
    • Z is C1-C3 alkyl substituted with 1-2 R12;
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12 is C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • B is a 6, 7, or 8 membered thiolactam,
      • wherein the thiolactam is saturated, partially saturated or unsaturated;
      • wherein each additional thiolactam carbon is substituted with 0-2 R11; and,
      • optionally, the thiolactam contains a heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)2—, and —
    • R10 is H, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, S(═O)2R17;
      • C1-C6 alkyl substituted with 0-1 R10a;
      • C6-C10 aryl substituted with 0-4 R10b;
      • C3-C10 carbocycle substituted with 0-3 R10b; or
      • 5 to 10 membered heterocycle optionally substituted with 0-3 R10b;
    • R10a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-4 R10b;
    • R10b, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, or CF3;
    • R11, at each occurrence, is independently selected from
      • C1-C4 alkoxy, Cl, F, Br, I, ═O, CN, NO2, NR18R19, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, CF3;
      • C1-C6 alkyl substituted with 0-1 R11a;
      • C6-C10 aryl substituted with 0-3 R11b;
      • C3-C10 carbocycle substituted with 0-3 R11b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R11b;
    • alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle or a benzo fused radical;
    • R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
    • R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • R14 is H, phenyl, benzyl, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
    • R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl);
    • R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl);
    • R17 is H, aryl, (aryl)CH2—, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
    • R18, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl); and
    • R19, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl); and
    • R19b is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or phenethyl.
  • [0909]
    [15] In a further preferred embodiment the present invention provides
    • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
    • R3 is —(CR7R7a)n—R4,
      • —(CR7R7a)n—S(CR7R7a)m—R4,
      • —(CR7R7a)n—O—(CR7R7a)m—R4, or
      • —(CR7R7a)n—N(R7b)—(CR7R7a)m—R4;
    • n is 0, 1, or 2;
    • m is 0, 1, or 2;
    • R3a is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, or butoxy;
    • R4 is H, OH, OR14a,
      • C1-C4 alkyl substituted with 0-2 R4a,
      • C2-C4 alkenyl substituted with 0-2 R4a,
      • C2-C4 alkynyl substituted with 0-2 R4a,
      • C3-C6 cycloalkyl substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, or
      • 5 to 10 membered heterocycle substituted with 0-3 R4b;
    • R4a, at each occurrence, is independently selected from is H, F, Cl, Br, I CF3,
      • C3-C10 carbocycle substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, or
      • 5 to 10 membered heterocycle substituted with 0-3 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • R5 is H, OR14;
      • C1-C6 alkyl substituted with 0-3 R5b;
      • C2-C6 alkenyl substituted with 0-3 R5b;
      • C2-C6 alkynyl substituted with 0-3 R5b;
      • C3-C10 carbocycle substituted with 0-3 R5c;
      • C6-C10 aryl substituted with 0-3 R5c; or
      • 5 to 10 membered heterocycle substituted with 0-3R5c;
    • R5a is H, OH, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, or C2-C4 alkenyloxy;
    • R5b, at each occurrence, is independently selected from:
      • H, C1-C6 alkyl, CF3, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16;
      • C3-C10 carbocycle substituted with 0-3 R5c;
      • C6-C10 aryl substituted with 0-3 R5c; or
      • 5 to 10 membered heterocycle substituted with 0-3 R5c;
    • R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • R6 is H, methyl, or ethyl;
    • R7, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, and C1-C4 alkyl;
    • R7a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, phenyl and C1-C4 alkyl;
    • R7b is independently selected from H, methyl, ethyl, propyl, and butyl;
    • W is —(CR8R8a)p—;
    • p is 0, 1, or 2;
    • R8 and R8a, at each occurrence, are independently selected from H, F, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl and C3-C6 cycloalkyl;
    • X is a bond;
      • C6-C10 aryl substituted with 0-3 RXb;
      • C3-C10 carbocycle substituted with 0-2 RXb; or
      • 5 to 10 membered heterocycle substituted with 0-2 RXb;
    • RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • Y is a bond or —(CR9R9a)t—V—(CR9R9a)u—;
    • t is 0, 1, or 2;
    • u is 0, 1, or 2;
    • R9 and R9a, at each occurrence, are independently selected from H, F, C1-C4 alkyl or C3-C6 cycloalkyl;
    • V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —N(R19)—, —C(═O)NR19b—, —NR19bC(═O)—, —NR19bS(═O)2—, —S(═O)2NR19b—, —NR19bS(═O)—, or —S(═O)NR19b—;
    • Z is C1-C3 alkyl substituted with 1-2 R12;
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12 is C6-C10 aryl substituted with 0-4 R12b;
      • C3-C10 carbocycle substituted with 0-4 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • B is a seven membered thiolactam,
      • wherein the thiolactam is saturated, partially saturated or unsaturated;
      • wherein each additional thiolactam carbon is substituted with 0-2 R1; and,
      • optionally, the thiolactam contains a heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)2—, and —N(R10)—;
    • R10 is H, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, S(═O)2R17;
      • C1-C6 alkyl substituted with 0-1 R10a;
      • C6-C10 aryl substituted with 0-4 R10b;
      • C3-C10 carbocycle substituted with 0-3 R10b; or
      • 5 to 10 membered heterocycle optionally substituted with 0-3 R10b;
    • R10a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-4 R10b;
    • R10b, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, or CF3;
    • R11, at each occurrence, is independently selected from
      • C1-C4 alkoxy, Cl, F, ═O, NR18R19, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, CF3;
      • C1-C6 alkyl substituted with 0-1 R11a;
      • C6-C10 aryl substituted with 0-3 R11b;
      • C3-C10 carbocycle substituted with 0-3 R11b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R11b;
    • alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle or a benzo fused radical;
    • R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
    • R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
    • R14 is H, phenyl, benzyl, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
    • R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl);
    • R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl);
    • R17 is H, aryl, (aryl)CH2—, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
    • R18, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl); and
    • R19, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl); and
    • R19b is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or phenethyl.
  • [0996]
    [16] In a further preferred embodiment the present invention provides
    • R3 is —(CR7R7a)n—R4,
      • —(CR7R7a)n—S—(CR7R7a)m—R4,
      • —(CR7R7a)n—O—(CR7R7a)m—R4, or
      • —(CR7R7a)n—N(R7b)-(CR7R7a)m—R4;
    • n is 0 or 1;
    • m is 0 or 1;
    • R3a is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, or butoxy;
    • R4 is H, OH,
      • C1-C4 alkyl substituted with 0-2 R4a,
      • C2-C4 alkenyl substituted with 0-2 R4a,
      • C2-C4 alkynyl substituted with 0-1 R4a,
      • C3-C6 cycloalkyl substituted with 0-3 R4b,
      • C6-C10 aryl substituted with 0-3 R4b, or
      • 5 to 10 membered heterocycle substituted with 0-3 R4b;
    • R4a, at each occurrence, is independently selected from is H, F, Cl, CF3,
      • C3-C6 cycloalkyl substituted with 0-3 R4b, phenyl substituted with 0-3 R4b, or
      • 5 to 6 membered heterocycle substituted with 0-3 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • R5 is H, OR14;
      • C1-C4 alkyl substituted with 0-3 R5b;
      • C2-C4 alkenyl substituted with 0-2 R5b; or
      • C2-C4 alkynyl substituted with 0-2 R5b;
    • R5a is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, or allyl;
    • R5b, at each occurrence, is independently selected from:
      • H, methyl, ethyl, propyl, butyl, CF3, OR14, ═O;
      • C3-C6 cycloalkyl substituted with 0-2 R5c;
      • phenyl substituted with 0-3 R5c; or
      • 5 to 6 membered heterocycle substituted with 0-2 R5c;
    • R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • R6 is H;
    • R7, at each occurrence, is independently selected from H, F, CF3, methyl, and ethyl;
    • R7a, at each occurrence, is independently selected from H, F, CF3, methyl, and ethyl;
    • R7b is independently selected from H, methyl, and ethyl;
    • W is a bond, —CH2—, —CH(CH3)—, —CH2CH2— or —CH(CH3)CH2—;
    • X is a bond;
      • phenyl substituted with 0-2 RXb;
      • C3-C6 cycloalkyl substituted with 0-2 RXb; or
      • 5 to 6 membered heterocycle substituted with 0-2 RXb;
    • RXb, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • Y is a bond, —CH2—V—, —V—, or —V—CH2—;
    • V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(CH3)—, or —N(CH2CH3)—,
    • Z is C1-C2 alkyl substituted with 1-2 R12;
      • C6-C10 aryl substituted with 0-4 R12b;
      • C3-C6 carbocycle substituted with 0-3 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12 is C6-C10 aryl substituted with 0-4 R12b;
      • C3-C6 carbocycle substituted with 0-3 R12b; or
      • 5 to 10 membered heterocycle substituted with 0-3 R12b;
    • R12b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • B is a seven membered thiolactam,
      • wherein the thiolactam is saturated, partially saturated or unsaturated;
      • wherein each additional thiolactam carbon is substituted with 0-2 R11; and,
      • optionally, the thiolactam contains a heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)2—, and —N(R10)—;
    • R10 is H, C(═O)R17, C(═O)OR17;
      • C1-C4 alkyl substituted with 0-1 R10a;
      • phenyl substituted with 0-4 R10b;
      • C3-C6 carbocycle substituted with 0-3 R10b; or
      • 5 to 6 membered heterocycle optionally substituted with 0-3 R10b;
    • R10a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-4 R10b;
    • R10b, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, C1-C3 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, or CF3;
    • R11, at each occurrence, is independently selected from
      • C1-C4 alkoxy, Cl, F, ═O, NR18R19, C(═O)R17, C(═O)OR17, CF3;
      • C1-C4 alkyl substituted with 0-1 R11a;
      • phenyl substituted with 0-3 R11b;
      • C3-C6 carbocycle substituted with 0-3 R11b; or
      • 5 to 6 membered heterocycle substituted with 0-3 R11b;
    • alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a benzo fused radical;
    • R11a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, F, ═O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
    • R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • R14 is H, phenyl, benzyl, C1-C4 alkyl, or C2-C4 alkoxyalkyl;
    • R15, at each occurrence, is independently selected from H, C1-C4 alkyl, benzyl, phenethyl, —C(═O)—(C1-C4 alkyl) and —S(═O)2—(C1-C4 alkyl);
    • R16, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, benzyl, phenethyl, —C(═O)—(C1-C4 alkyl) and —S(═O)2—(C1-C4 alkyl);
    • R17 is H, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl, (4-methylphenyl)methyl, (4-trifluorophenyl)methyl, methyl, ethyl, propyl, butyl, methoxymethyl, methyoxyethyl, ethoxymethyl, or ethoxyethyl;
    • R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
    • R19, at each occurrence, is independently selected from H, methyl, and ethyl.
  • [1072]
    [17] In a more preferred embodiment the present invention provides
    • or a pharmaceutically acceptable salt or prodrug thereof, wherein:
    • R3 is —CH3, —CH2CH3, —CH2CH2CH3, —CH2CH2CH2CH3, —CH2(CH3)2, —CH(CH3)CH2CH3, —CH2CH(CH3)2, —CH2C(CH3)3, —CF3, —CH2CF3, —CH2CH2CF3, —CH2CH2CH2CF3, —CH═CH2, —CH2CH═CH2, —CH2C(CH3)═CH2, —CH2CH═C(CH3)2, —CH2CH2CH═CH2, —CH2CH2C(CH3)═CH2, —CH2CH2CH═C(CH3)2, cis-CH2CH═CH(CH3), cis-CH2CH2CH═CH(CH3), trans-CH2CH═CH(CH3), trans-CH2CH2CH═CH(CH3); —C═CH, —CH2C≡CH, —CH2C═C(CH3), cyclopropyl-CH2—, cyclobutyl-CH2—, cyclopentyl-CH2—, cyclohexyl-CH2—, cyclopropyl-CH2CH2—, cyclobutyl-CH2CH2—, cyclopentyl-CH2CH2—, cyclohexyl-CH2CH2—, phenyl-CH2—, (2-F-phenyl)CH2—, (3-F-phenyl)CH2—, (4-F-phenyl)CH2—, (2-Cl-phenyl)CH2—, (3-Cl-phenyl)CH2—, (4-Cl-phenyl)CH2—, (2,3-diF-phenyl)CH2—, (2,4-diF-phenyl)CH2—, (2,5-diF-phenyl)CH2—, (2,6-diF-phenyl)CH2—, (3,4-diF-phenyl)CH2—, (3,5-diF-phenyl)CH2—, (2,3-diCl-phenyl)CH2—, (2,4-diCl-phenyl)CH2—, (2,5-diCl-phenyl)CH2—, (2,6-diCl-phenyl)CH2—, (3,4-diCl-phenyl)CH2—, (3,5-diCl-phenyl)CH2—, (3-F-4-Cl-phenyl)CH2—, (3-F-5-Cl-phenyl)CH2—, (3-Cl-4-F-phenyl)CH2—, phenyl-CH2CH2—, (2-F-phenyl)CH2CH2—, (3-F-phenyl)CH2CH2—, (4-F-phenyl)CH2CH2—, (2-Cl-phenyl)CH2CH2—, (3-Cl-phenyl)CH2CH2—, (4-Cl-phenyl)CH2CH2—, (2,3-diF-phenyl)CH2CH2—, (2,4-diF-phenyl)CH2CH2—, (2,5-diF-phenyl)CH2CH2—, (2,6-diF-phenyl)CH2CH2—, (3,4-diF-phenyl)CH2CH2—, (3,5-diF-phenyl)CH2CH2—, (2,3-diCl-phenyl)CH2CH2—, (2,4-diCl-phenyl)CH2CH2—, (2,5-diCl-phenyl)CH2CH2—, (2,6-diCl-phenyl)CH2CH2—, (3,4-diCl-phenyl)CH2CH2—, (3,5-diCl-phenyl)CH2CH2—, (3-F-4-Cl-phenyl)CH2CH2—, (3-F-5-Cl-phenyl)CH2CH2—, or
    • R5 is —CH3, —CH2CH3, —CH2CH2CH3, —CH2(CH3)2, —CH2CH2CH2CH3, —CH(CH3)CH2CH3, —CH2CH(CH3)2, —CH2C(CH3)3, —CH2CH2CH2CH2CH3, —CH(CH3)CH2CH2CH3, —CH2CH(CH3)CH2CH3, —CH2CH2CH(CH3)2, —CH(CH2CH3)2, —CF3, —CH2CF3, —CH2CH2CF3, —CH2CH2CH2CF3, —CH2CH2CH2CH2CF3, —CH═CH2, —CH2CH═CH2, —CH═CHCH3, cis-CH2CH═CH(CH3), trans-CH2CH═CH(CH3), trans-CH2CH═CH(C6H5), —CH2CH═C(CH3)2, cis-CH2CH═CHCH2CH3, trans-CH2CH═CHCH2CH3, cis-CH2CH2CH═CH(CH3), trans-CH2CH2CH═CH(CH3), trans-CH2CH═CHCH2(C6H5), —C═CH, —CH2C≡CH, —CH2C≡C(CH3), —CH2C≡C(C6H5) —CH2CH2C≡CH, —CH2CH2C≡C(CH3), —CH2CH2C≡C(C6H5) —CH2CH2CH2C≡CH, —CH2CH2CH2C≡C(CH3), —CH2CH2CH2C≡C(C6H5) cyclopropyl-CH2—, cyclobutyl-CH2—, cyclopentyl-CH2—, cyclohexyl-CH2—, (2-CH3-cyclopropyl)CH2—, (3-CH3-cyclobutyl)CH2—, cyclopropyl-CH2CH2—, cyclobutyl-CH2CH2—, cyclopentyl-CH2CH2—, cyclohexyl-CH2CH2—, (2-CH3-cyclopropyl)CH2CH2—, (3-CH3-cyclobutyl)CH2CH2—, phenyl-CH2—, (2-F-phenyl)CH2—, (3-F-phenyl)CH2—, (4-F-phenyl)CH2—, furanyl-CH2—, thienyl-CH2—, pyridyl-CH2—, 1-imidazolyl-CH2—, oxazolyl-CH2—, isoxazolyl-CH2—, phenyl-CH2CH2—, (2-F-phenyl)CH2CH2—, (3-F-phenyl)CH2CH2—, (4-F-phenyl)CH2CH2—, furanyl-CH2CH2—, thienyl-CH2CH2—, pyridyl-CH2CH2—, 1-imidazolyl-CH2CH2—, oxazolyl-CH2CH2—, isoxazolyl-CH2CH2—,
    • W is a bond, —CH2—, or —CH(CH3)—;
    • X is a bond;
    • Y is a bond, —CH2—V—, —V—, or —V—CH2—;
    • V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, or —N(CH3)—,
    • Z is phenyl 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-4-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF3O-phenyl, 3-CF3O-phenyl, 4-CF3O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholino, N-piperinyl, phenyl-CH2—, (2-F-phenyl)CH2—, (3-F-phenyl)CH2—, (4-F-phenyl)CH2—, (2-Cl-phenyl)CH2—, (3-Cl-phenyl)CH2—, (4-Cl-phenyl)CH2—, (2,3-diF-phenyl)CH2—, (2,4-diF-phenyl)CH2—, (2,5-diF-phenyl)CH2—, (2,6-diF-phenyl)CH2—, (3,4-diF-phenyl)CH2—, (3,5-diF-phenyl)CH2—, (2,3-diCl-phenyl)CH2—, (2,4-diCl-phenyl)CH2—, (2,5-diCl-phenyl)CH2—, (2,6-diCl-phenyl)CH2—, (3,4-diCl-phenyl)CH2—, (3,5-diCl-phenyl)CH2—, (3-F-4-Cl-phenyl)CH2—, (3-F-5-Cl-phenyl)CH2—, (3-Cl-4-F-phenyl)CH2—, (2-MeO-phenyl)CH2—, (3-MeO-phenyl)CH2—, (4-MeO-phenyl)CH2—, (2-Me-phenyl)CH2—, (3-Me-phenyl)CH2—, (4-Me-phenyl)CH2—, (2-MeS-phenyl)CH2—, (3-MeS-phenyl)CH2—, 4-MeS-phenyl)CH2—, (2-CF3O-phenyl)CH2—, (3-CF3O-phenyl)CH2—, (4-CF3O-phenyl)CH2—, (furanyl)CH2—, (thienyl)CH2—, (pyridyl)CH2—, (2-Me-pyridyl)CH2—, (3-Me-pyridyl)CH2—, (4-Me-pyridyl)CH2—, (1-imidazolyl)CH2—, (oxazolyl)CH2—, (isoxazolyl)CH2—, (1-benzimidazolyl)CH2—, (cyclopropyl)CH2—, (cyclobutyl)CH2—, (cyclopentyl)CH2—, (cyclohexyl)CH2—, (morpholino)CH2—, (N-pipridinyl)CH2—, phenyl-CH2CH2—, (phenyl)2CHCH2—, (2-F-phenyl)CH2CH2—, (3-F-phenyl)CH2CH2—, (4-F-phenyl)CH2CH2—, (2-Cl-phenyl)CH2CH2—, (3-Cl-phenyl)CH2CH2—, (4-Cl-phenyl)CH2CH2—, (2,3-diF-phenyl)CH2CH2—, (2,4-diF-phenyl)CH2CH2—, (2,5-diF-phenyl)CH2CH2—, (2,6-diF-phenyl)CH2CH2—, (3,4-diF-phenyl)CH2CH2—, (3,5-diF-phenyl)CH2CH2—, (2,3-diCl-phenyl)CH2CH2—, (2,4-diCl-phenyl)CH2CH2—, (2,5-diCl-phenyl)CH2CH2—, (2,6-diCl-phenyl)CH2CH2—, (3,4-diCl-phenyl)CH2CH2—, (3,5-diCl-phenyl)CH2CH2—, (3-F-4-Cl-phenyl)CH2CH2—, (3-F-5-Cl-phenyl)CH2CH2—, (3-Cl-4-F-phenyl)CH2CH2—, (2-MeO-phenyl)CH2CH2—, (3-MeO-phenyl)CH2CH2—, (4-MeO-phenyl)CH2CH2—, (2-Me-phenyl)CH2CH2—, (3-Me-phenyl)CH2CH2—, (4-Me-phenyl)CH2CH2—, (2-MeS-phenyl)CH2CH2—, (3-MeS-phenyl)CH2CH2—, (4-MeS-phenyl)CH2CH2—, (2-CF3O-phenyl)CH2CH2—, (3-CF3O-phenyl)CH2CH2—, (4-CF3O-phenyl)CH2CH2—, (furanyl)CH2CH2—, (thienyl)CH2CH2—, (pyridyl)CH2CH2—, (2-Me-pyridyl)CH2CH2—, (3-Me-pyridyl)CH2CH2—, (4-Me-pyridyl)CH2CH2—, (imidazolyl)CH2CH2—, (oxazolyl)CH2CH2—, (isoxazolyl)CH2CH2—, (benzimidazolyl)CH2CH2—, (cyclopropyl)CH2CH2—, (cyclobutyl)CH2CH2—, (cyclopentyl)CH2CH2—, (cyclohexyl)CH2CH2—, (morpholino)CH2CH2—, (N-pipridinyl)CH2CH2—,
    • B is a seven membered thiolactam,
      • wherein the thiolactam is saturated, partially saturated or unsaturated;
      • wherein each additional thiolactam carbon is substituted with 0-2 R11; and,
      • optionally, the thiolactam contains a heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)2—, and —N(R10)—;
    • R10 is H, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH2—, (4-F-phenyl)CH2CH2—, 4-Cl-phenyl, (4-Cl-phenyl)CH2—, (4-Cl-phenyl)CH2CH2—, 4-CH3-phenyl, (4-CH3-phenyl)CH2—, (4-CH3-phenyl)CH2CH2—, 4-CF3-phenyl, (4-CF3-phenyl)CH2—, or (4-CF3-phenyl)CH2CH2—;
    • R11 at each occurrence, is independently selected from H, ═O, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH2—, (4-F-phenyl)CH2CH2—, 4-Cl-phenyl, (4-Cl-phenyl)CH2—, (4-Cl-phenyl)CH2CH2—, 4-CH3-phenyl, (4-CH3-phenyl)CH2—, (4-CH3-phenyl)CH2CH2—, 4-CF3-phenyl, (4-CF3-phenyl)CH2—, or (4-CF3-phenyl)CH2CH2—; and alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a benzo fused radical.
  • [1087]
    [18] In a futher more preferred embodiment the present invention provides
    • B is
  • [1089]
    [19] In another even more preferred embodiment the present invention provides compounds of Formula (I) selected from:
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)pyrid-5-ylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)pyrid-5-ylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)pyrid-5-ylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(4-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2S,3R) N1-[(3S)-hexahydro-1-(3-(2-tetrazolylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(propyl)-3-(2-methylpropyl)-butanediamide;
    • (2S,3R) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(propyl)-3-(2-methylpropyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; and
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(phenethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-((4-fluorophenyl)methyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(cyclopropylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(cyclobutylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(cyclopentylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(cyclohexylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(cyclopropylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(cyclobutylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(cyclopentylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(cyclohexylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(phenethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-((4-fluorophenyl)methyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(cyclopropylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(cyclobutylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(cyclopentylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(cyclohexylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(cyclopropylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(cyclobutylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(cyclopentylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(cyclohexylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(phenethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-((4-fluorophenyl)methyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(cyclopropylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(cyclobutylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(cyclopentylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(cyclohexylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(cyclopropylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(cyclobutylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(cyclopentylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; and
    • (2R,3S) N1-[(3S)-hexahydro-1-(cyclohexylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide.
  • [1229]
    [20] In another even more preferred embodiment the present invention provides compounds of Formula (I) selected from:
    • (2R,3S) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-S-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-S-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-S-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-S-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-S-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-S-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; and
    • (2R,3S) N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3-dihydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; and
    • (2R,3S) N1-[1,3-dihydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide.
  • [1358]
    [21] In another even more preferred embodiment the present invention provides compounds of Formula (I) selected from:
    • (2R,3S) N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-S-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-S-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-S-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-S-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-S-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-S-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-S-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-S-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[(6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; and
    • (2R,3S) N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide.
    • (2R,3S) N1-[6,7-dihydro-5-(benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(phenethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-((4-fluorophenyl)methyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(cyclopropylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(cyclobutylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(cyclopentylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(cyclohexylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(cyclopropylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(cyclobutylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(cyclopentylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(cyclohexylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(phenethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-((4-fluorophenyl)methyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(cyclopropylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(cyclobutylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(cyclopentylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(cyclohexylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(cyclopropylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(cyclobutylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(cyclopentylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(cyclohexylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(phenethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-((4-fluorophenyl)methyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(cyclopropylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(cyclobutylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(cyclopentylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-S-(cyclohexylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(cyclopropylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(cyclobutylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[6,7-dihydro-5-(cyclopentylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; and
    • (2R,3S) N1-[6,7-dihydro-5-(cyclohexylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide.
  • [1487]
    [22] In another even more preferred embodiment the present invention provides compounds of Formula (I) selected from:
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-S-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; and
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(1,3,4,5-tetrahydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; and
    • (2R,3S) N1-[1,3,4,5-tetrahydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide.
  • [1616]
    [23] In another even more preferred embodiment the present invention provides compounds of Formula (I) selected from:
    • (2R,3S) N1-[(3S)-hexahydro-1-(3,3-diphenylpropyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(phenyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(methyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(methoxy)-N-4-(methyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(methoxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(amino)-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(allyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(butyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(2-furylmethyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide;
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(cyclopentyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide; and
    • (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(cinnamyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide.
  • [1640]
    In another preferred embodiment of the present invention, Q is N(OH)H.
  • [1641]
    In another preferred embodiment of the present invention, Q is NH2.
  • [1642]
    In another preferred embodiment
    • R3 is R4,
    • R3a is H, methyl, ethyl, propyl, or butyl;
    • R4 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl
    • R5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl
    • R5a is H, methyl, ethyl, propyl, or butyl; and
    • the total number of carbon atoms in R3, R3a, R5 and R5a equals seven or more.
  • [1649]
    In another preferred embodiment
    • R3 is R4;
    • R3a is H;
    • R4 is C1-C4 alkyl substituted with 1-2 R4a,
    • R4a, at each occurrence, is independently selected from
      • C3-C6 cycloalkyl substituted with 0-3 R4b,
      • phenyl substituted with 0-3 R4b, or
      • 5 to 6 membered heterocycle substituted with 0-3 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • R5 is C2-C4 alkyl substituted with 0-3 R5b;
      • C2-C4 alkenyl substituted with 0-2 R5b; or
      • C2-C4 alkynyl substituted with 0-2 R5b;
    • R5b, at each occurrence, is independently selected from:
      • H, methyl, ethyl, propyl, butyl, CF3, OR14, ═O;
      • C3-C6 cycloalkyl substituted with 0-2 R5c;
      • phenyl substituted with 0-3 R5c; or
      • 5 to 6 membered heterocycle substituted with 0-2 R5c; and
    • R5c, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy.
  • [1667]
    In another preferred embodiment
    • R3 is R4;
    • R3a is H;
    • R4 is C2-C4 alkyl substituted with 0-2 R4a,
      • C2-C4 alkenyl substituted with 0-2 R4a,
      • C2-C4 alkynyl substituted with 0-2 R4a,
    • R4a, at each occurrence, is independently selected from is H, F, CF3,
      • C3-C6 cycloalkyl substituted with 0-3 R4b,
      • phenyl substituted with 0-3 R4b, or
      • 5 to 6 membered heterocycle substituted with 0-3 R4b;
    • R4b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
    • R5 is C1-C4 alkyl substituted with 1-2 R5b;
    • R5b, at each occurrence, is independently selected from:
      • C3-C6 cycloalkyl substituted with 0-2 R5c;
      • phenyl substituted with 0-3 R5c; or
      • 5 to 6 membered heterocycle substituted with 0-2 R5c; and
    • R5c, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy.
  • [1684]
    In another preferred embodiment
    • W is —(CH2)p—;
    • p is 1, 2, or 3;
    • X is a bond;
      • phenyl substituted with 0-2 RXb;
      • C3-C6 cycloalkyl substituted with 0-2 RXb; or
      • 5 to 6 membered heterocycle substituted with 0-2 RXb;
      • wherein the 5 to 6 membered heterocycle does not contain an oxo or imino substitued ring atom; and
    • RXb at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy.
  • [1693]
    In another preferred embodiment when R1 is H, R2 is hydroxy, and R11 is H, then X is not a bond.
  • [1694]
    It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to descibe additional even more preferred embodiments of the present invention.
  • [1695]
    In a second embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.
  • [1696]
    In a third embodiment, the present invention provides a method for the treatment of neurological disorders associated with β-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I).
  • [1697]
    In a preferred embodiment the neurological disorder associated with β-amyloid production is Alzheimer's Disease.
  • [1698]
    In a fourth embodiment, the present invention provides a method for the treatment of neurological disorders associated with β-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a metalloprotease inhibitor which inhibits γ-secretase activity.
  • [1699]
    In a preferred embodiment the neurological disorder associated with β-amyloid production is Alzheimer's Disease.
  • [1700]
    In a preferred embodiment, the metalloprotease inhibitor is a hydroxamic acid.
  • [1701]
    In a more preferred embodiment, the metalloprotease inhibitor is a hydroxamic acid with an IC50 value of less than 10 μM in the Aβ immunoprecipitation assay.
  • [1702]
    In a fifth embodiment, the present invention provides a method for inhibiting γ-secretase activity for the treatment of a physiological disorder associated with inhibiting γ-secretase activity comprising administering to a host in need of such inhibition a therapeutically effective amount of a compound of Formula (I) that inhibits γ-secretase activity.
  • [1703]
    In a preferred embodiment the physiological disorder associated with inhibiting γ-secretase activity is Alzheimer's Disease.
  • [1704]
    In a sixth embodiment, the present invention provides a compound of Formula (I) for use in therapy.
  • [1705]
    In a preferred embodiment the present invention provides a compound of Formula (I) for use in therapy of Alzheimer's Disease.
  • [1706]
    In a seventh embodiment, the present invention provides for the use of a compound of Formula (I) for the manufacture of a medicament for the treatment of Alzheimer's Disease.
  • Definitions
  • [1707]
    As used herein, the term “Aβ” denotes the protein designated Aβ, β-amyloid peptide, and sometimes β/A4, in the art. Aβ is an approximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acids found in amyloid plaques, the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, venules. The isolation and sequence data for the first 28 amino acids are described in U.S. Pat. No. 4,666,829. The 43 amino acid sequence is:
    1
    Asp \Ala \Glu \Phe \Arg \His \Asp \Ser \Gly \Tyr
    11
    Glu \Val \His \His \Gln \Lys \Leu \Val \Phe \Phe
    21
    Ala \Glu \Asp \Val \Gly \Ser \Asn \Lys \Gly \Ala
    31
    Ile \Ile \Gly \Leu \Met \Val \Gly \Gly \Val \Val
    41
    Ile \Ala \Thr.

    However, a skilled artisan knows that fragments generated by enzymatic degradation can result in loss of amino acids 1-10 and/or amino acids 39-43. Thus, an amino acid sequence 1-43 represents the maximum sequence of amino acids for Aβ peptide.
  • [1708]
    The term “APP”, as used herein, refers to the protein known in the art as b amyloid precursor protein. This protein is the precursor for Aβ and through the activity of “secretase” enzymes, as used herein, it is processed into Aβ. Differing secretase enzymes, known in the art, have been designated b secretase, generating the N-terminus of Aβ, a secretase cleaving around the 16/17 peptide bond in Aβ, and “γ secretases”, as used herein, generating C-terminal Aβ fragments ending at position 38, 39, 40, 41, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides.
  • [1709]
    The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
  • [1710]
    The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced.
  • [1711]
    When any variable (e.g., R5b) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R5b, then said group may optionally be substituted with up to two R5b groups and R5b at each occurrence is selected independently from the definition of R5b. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • [1712]
    When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • [1713]
    As used herein, “alkyl” or “alkylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, “C1-C6 alkyl” denotes alkyl having 1 to 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl. Preferred “alkyl” group, unless otherwise specified, is “C1-C4 alkyl”.
  • [1714]
    As used herein, “alkenyl” or “alkenylene” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain. Examples of “C2-C6 alkenyl” include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 2-pentenyl, 3-pentenyl, hexenyl, and the like.
  • [1715]
    As used herein, “alkynyl” or “alkynylene” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
  • [1716]
    “Alkoxy” or “alkyloxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy. Similarly, “alkylthio” or “thioalkoxy” is represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
  • [1717]
    “Halo” or halogen as used herein refers to fluoro, chloro, bromo, and iodo. Unless otherwise specified, preferred halo is fluoro and chloro. “Counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
  • [1718]
    “Haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example —CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, heptafluoropropyl, and heptachloropropyl. “Haloalkoxy” is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge; for example trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy, and the like. “Halothioalkoxy” is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
  • [1719]
    “Cycloalkyl” is intended to include saturated ring groups, having the specified number of carbon atoms. For example, “C3-C6 cycloalkyl” denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • [1720]
    As used herein, “carbocycle” is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). Preferred “carbocycle” are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • [1721]
    As used herein, the term “heterocycle” or “heterocyclic ring” is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms, preferably 1, 2, or 3 heteroatoms, independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.
  • [1722]
    Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 61-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl. Preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl; more preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, and tetrazolyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
  • [1723]
    As used herein, the term “aryl”, “C6-C10 aryl” or aromatic residue, is intended to mean an aromatic moiety containing the specified number of carbon atoms; for example phenyl, pyridinyl or naphthyl. Unless otherwise specified, “aryl” may be unsubstituted or substituted with 0 to 3 groups selected from H, OH, OCH3, Cl, F, Br, I, CN, NO2, NH2, N(CH3)H, N(CH3)2, CF3, OCF3, C(═O)CH3, SCH3, S(═O)CH3, S(═O)2CH3, CH3, CH2CH3, CO2H, and CO2CH3.
  • [1724]
    The phrase “additional lactam carbons and thiolactam carbons”, as used herein, is intended to denote the number of optional carbon atoms in the lactam ring or thiolactam ring B of Formula (I). Formula (I″):
    represents the lactam ring B of Formula (I). The ring numbering shown for lactams of Formula (I″) applies to analogous thiolactams. Additional lactam carbons are carbons in lactam ring B other than the carbons numbered 2 and 3 in the backbone of the formula. The additional lactam carbons may be optionally replaced by a heteroatom selected from oxygen, nitrogen and sulfur. Lactam ring B contains 1, 2, 3, 4, 5, 6 or 7 optional carbons, wherein one optional carbon may optionally be replaced by a heteroatom, such that the total number of members of lactam ring B, including atoms numbered 1, 2 and 3 in the backbone, does not exceed 10. It is preferred that the total number of atoms of lactam ring B is 6, 7 or 8; it is more preferred that the total number of atoms of lactam ring B is seven. Examples of lactam ring B include:
    and their thiolactam counterparts. The examples are not intended to limit the invention. Preferred examples of lactam ring B are B1, B2, B5, B6, B8, B9, B13, and B16; more preferred examples of lactam ring B are B1, B6, B8, B9, and B13. Preferred examples of substituent R10 or R11 on lactam B are methyl, ethyl, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl, and (4-trifluorophenyl)methyl.
  • [1725]
    The compounds herein described may have asymmetric centers. One enantiomer of a compound of Formula (I) may display superior chemical activity over the opposite enantiomer. For example carbon 3 of lactam ring B Formula (I″) may exist in either an S or R configuration. Thus, an R or S configuration at carbon 3 in Formula (I″) is considered part of the invention. An example of such configuration includes,
    but is not intended to be limited to this example of ring B. When required, separation of the racemic material can be achieved by methods known in the art. Additionally, the carbon atoms to which R3 and R5 are attached may describe chiral carbons which may display superior chemical activity over the opposite enantiomer. For example, where R3 and R5 are not H, then the configuration of the two centers may be described as (2R,3R), (2R,3S), (2S,3R), or (2S,3S). All configurations are considered part of the invention; however, the (2R,3S) and the (2S,3R) are preferred and the (2R,3S) is more preferred.
  • [1726]
    The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • [1727]
    As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and
  • [1728]
    the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • [1729]
    The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
  • [1730]
    “Prodrugs” are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like.
  • [1731]
    “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • Synthesis
  • [1732]
    The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
  • [1733]
    The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
  • [1734]
    Methods for the synthesis of succinylamino lactams are known in the art and are disclosed in a number of references including PCT publication number WO 96/29313, which is hereby incorporated by reference.
  • [1735]
    Disubstituted succinate derivatives can be prepared by a number of known procedures. The procedure of Evans (D. A. Evans et al, Org. Synth. 86, p 83 (1990)) is outlined in Scheme 1 where acylation of an oxazolidinone with an acylating agent such as an acid chloride provides structures 1. Alkylation to form 2 followed by cleavage of the chiral auxiliary and subsequent alkylation of the dianion of the carboxylic acid 3 provides a variety of disubstituted succinates which can be separated and incorporated into structures of Formula (I) by those skilled in the art. Additional examples are found in P. Becket, M. J. Crimmin, M. H. Davis, Z. Spavold, Synlett, (1993), 137-138, incorporated herein by reference.
  • [1736]
    Diastereomerically pure succinate derivatives can be accessed using the chemistry outlined below, adapted from P. Becket, M. J. Crimmin, M. H. Davis, Z. Spavold, Synlett, (1993), 137-138 incorporated herein by reference. This reference provides the synthesis below to obtain compound 9. Compound 11 is used as an intermediate and is prepared from 9 by hydrogenation of the allyl group followed by coupling of 9-fluorenemethanol under standard conditions using DCC and DMAP in CH2Cl2. Deprotection of the tert-butyl ester is accomplished by treatment with 50% trifluoroacetic acid.
  • [1737]
    Additional methods useful for the preparation of succinate derivatives are known by those skilled in the art. Such references include, McClure and Axt, Bioorganic & Medicinal Chemistry Letters, 8 (1998) 143-146; Jacobson and Reddy, Tetrahedron Letters, Vol 37, No. 46, 8263-8266 (1996); Pratt et al., SYNLETT, May 1998, p. 531; WO 97/18207; and WO 98/51665. The synthetic disclosures of WO97/18207 and WO 98/51665 are hereby incorporated by reference.
  • [1738]
    A variety of compounds of Formula (I) can be prepared by methods described in Scheme 4. The protected α-amine 3 of the α-amino-ε-caprolactam can be prepared by methods well known in the literature for amino protecting groups as discussed in Theodora W. Greene's book “Protective Groups in Organic Synthesis”, like N-Boc using di-t-butyldicarbonate in an appropriate solvent like DMSO. A sulfur atom can be introduced into the ring providing L-α-amino-β-thio-ε-caprolactam according to the procedure in S. A. Ahmed et al, FEBS Letters, (1984), vol. 174, pages 76-9 (Scheme 3). One skilled in the art can extend this methodology to the synthesis of β-amino and oxygen containing rings by analogy. The sulfur-containing molecules can also be oxidized to the sulfoxide and sulfone by methods known to one skilled in the art.
  • [1739]
    The lactam nitrogen of compound 13 can be alkylated by generating the anion with bases such as LDA, lithium bis(trimethylsilyl)amide or sodium hydride in solvents like THF, with or without cosolvents such as DMPU or HMPA and reacting this with a variety of groups containing leaving groups (X″) like bromide, iodide, mesylate or tosylate. Alkylating agents such as α-bromo amides, ketones and acids can be prepared by a number of literature methods including halogenation of amino acids by diazotization or are commercially available. Other suitable alkylating agents such as alkyl, allylic and benzylic halides can be formed form a variety of precursors such as free-radical addition of halides or activation of alcohols, and other chemistries known to those skilled in the art. For discussion of these types of reactions, see Carey, F. A. and Sundberg, R. J., Advanced Organic Chemistry, Part A, New York: Plenum Press, 1990, pages 304-305, 342-347, 695-698.
  • [1740]
    The N-Boc protecting group can be removed by any number of methods well known in the literature like TFA in methylene chloride to give the compound 15. The amine 15 can be coupled to an appropriately substituted carboxylic acid or acid chloride by methods well described in the literature for making amide bonds, like TBTU in DMF with a base like NMM to give the elaborated compound 16. Compounds 16 can be alkylated using standard bases like LDA, NaH, or NaHMDS to deprotonate the amide followed by addition of an alkylating agent with an appropriate leaving group like halide, mesylate, or triflate in an appropriate solvent to provide compounds 17 with an R6 substituent. The t-butyl ester is then removed by treatment with TFA in ethylene chloride to give the carboxylic acid 17.
  • [1741]
    The final compounds 18 were prepared by treating the activated carboxylic acid of 17 with an appropriately substituted amine. For instance, activation of the carboxylic acid with HATU (O-(7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate) or PyBOP (benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate) or other coupling agents known to those skilled in the art allows condensation with ammonia to form primary amides. Similarly, condensation of the activated acid with hydroxylamine hydrochloride provides the hydroxamic acid, or reaction with a primary or secondary amine provides the substituted amine derivative.
  • [1742]
    Activation of the acid with PyBrOP (bromo-tris-pyrrolidino-phosphonium hexafluorophosphate) followed by addition of an alcohol and 4-dimethylaminopyridine allows formation of the ester directly. For additional acylation reactions see for example Carey, F. A. and Sundberg, R. J., Advanced Organic Chemistry, Part A, New York: Plenum Press, 1990, pages 475-479.
  • [1743]
    Additional Examples of compounds of Formula (I) can be prepared as shown in Scheme 5. A suitable resin for solid phase synthesis such as Fmoc (Fluorenylmethylcarbonyl)-protected hydroxylamine bound to polystyrene beads can be purchased from Novabiochem, Inc. Deprotection of the Fmoc group under standard conditions using 20% piperidine in DMF provides trityl-linked hydroxylamine resin. Coupling of a fluorenylmethyl-protected succinic acid derivative such as 20 with a coupling agent such as HATU in a suitable solvent like DMF or N-methylpyrrolidinone provides the support-bound hydroxamate 21. The Fluorenylmethyl ester can be removed using 20% piperidine in DMF to provide the free carboxylic acid which can be coupled to amines like the caprolactam 22 (which is available using chemistry outlined in Scheme 4) using PyBOP (benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate) and a suitable base like DIEA in DMF or NMP. The support-bound intermediate 23 can then be elaborated to biaryl structures of the type 24 using typical Suzuki coupling conditions employing a catalyst such as Palladium complexes like tetrakis(triphenylphosphine)-palladium with 2M aqueous sodium carbonate as a base in a suitable solvent like THF or DME and an excess of a boronic acid. The final compounds are liberated from the support employing dilute (5%) trifluoroacetic acid in CH2CL2 and purified by conventional chromatography.
    General Procedure for Solid-Phase Synthesis According to Scheme 5.
  • [1744]
    Resin 20 of Scheme 5: Fmoc-protected resin 19 (2.0 g, 0.78 mmol/g, 1.56 mmol) is purchased from Novabiochem and swelled in 20 ml of CH2Cl2 for 1 hour. The CH2Cl2 is removed and the resin is then treated with 25% v/v piperidine in DMF (8 mL) and allowed to shake slowly for 16 h. The solvent was removed by filtration and the resin was shaken with an additional 8 mL of 25% v/v piperidine in DMF for 2 h at rt. The solvents were removed by filtration, and the resin 20 was rinsed 3× with 20 mL of DMF, 3× with 20 mL of methanol, and 3× with 20 mL of CH2Cl2 and dried in vacuo.
  • [1745]
    Succinate 10 of Scheme 2: Succinate 9 is prepared according to the literature procedure (P. Becket, M. J. Crimmin, M. H. Davis, Z. Spavold, Synlett, (1993), 137-138). Succinate 9 (17.8 g, 66 mmol) is dissolved in 250 mL of ethyl acetate and placed in a Parr shaker bottle. To the solution is added 890 mg of 5% palladium on carbon, and the bottle is pressurized to 40 psi with hydrogen gas and shaken for 2.5 h at rt. The hydrogen is removed and the palladium catalyst is removed by filtration through a pad of celite. Concentration of the ethyl acetate solution provides 17.5 g (98%) of succinate 10. No further purification is necessary. MS (M-H)+=271.
  • [1746]
    Succinate 21 of Scheme 5: Succinate 10 (6.3 g, 23.1 mmol) is dissolved in 125 mL of CH2Cl2 and 4.8 g (23.3 mmol) of dicyclohexylcarbodiimide is added. The solution is stirred at rt for 30 min and then 4.6 g (23.4 mmol) of 9-fluorenemethanol is added followed by 122 mg (1 mmol) of 4-dimethylaminopyridine. After 5 h of stirring at rt, the reaction solution was diluted with an additional 100 mL of CH2Cl2 and filtered through a pad of celite to remove precipitated dicyclohexylurea. The solution was then washed 3× with 50 mL of a 1N HCl solution, 3× with 50 mL of a saturated sodium bicarbonate solution, and 2× with 50 mL of brine. The crude product was dried over MgSO4 and soncentrated onto 15 g of silica gel. Chromatography eluting with a gradient of 2.5% to 5% ethyl acetate/hexanes provided 6.4 g (61%) of the diester as an oil. The purified diester (6.4 g 14.2 mmol) is then dissolved in 25 mL of CH2Cl2, 25 mL of trifluoroacetic acid is added, and the reaction solution is stirred at rt for 2 h. The reaction solution is directly concentrated in vacuo to an oil which is then redissolved in 25 mL of toluene and reconcentrated, followed by drying in vacuo to provide 6.3 g (98%) of the desired succinate 9 as an oil which solidifies on standing. MS (M+Na)+=471, (M+2Na)+=439.
  • [1747]
    Caprolactam 23 of Scheme 5: Boc-caprolactam 14 (5.0 g 21.9 mmol) is dissolved in 60 mL of THF and chilled to −78° C. To the chilled solution is added 24 mL of a 1.0 M solution of lithium bis(trimethylsilyl)amide in THF, and the solution was brounght to 0° C. and stirred for 15 min. To the anion solution was added 6.5 g (22 mmol) of 3-iodobenzyl bromide (Aldrich) and the the solution was allowed to warm to rt and stirred for 18 h. The reaction solution was diluted with 50 mL of water and extracted 3× with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude product was purified by chromatography eluting with a gradient of 5-20% ethyl acetate/hexanes to afford 7.0 g (72%) of the title compound as a white solid. MS (M+Na)+=467.
  • [1748]
    Resin 22 of Scheme 5: Resin 22 (2.0 g, 0.78 mmol/g, 1.56 mmol) was swollen in 3 mL of DMF. In a separate flask, 1.85 g (4.68 mmol) of succinate 21 was dissolved in 3 mL of DMF and 2.5 ml of N,N-diisopropylethylamine (14 mmol) wsa added, followed by 1.81 g (4.68 mmol) of HATU. The solution containing the active ester was added to the slurried resin and the reaction suspension was slowly shaken for 18 h. The resin was then washed 3× with 20 mL of DMF, 3× with 20 mL of methanol, and 3× with 20 mL of CH2Cl2. Loading of the resin was determined by Fmoc quantitation to be 0.25 mmol/g, see Reddy, M. P.; Voelker, P. J. Int. J. Pept. Protein Res. 1998, 31, 345-348.
  • [1749]
    Resin 24 of Scheme 5: Resin 22 (2.0 g, 0.25 mmol/g, 0.5 mmol) was suspended in 10 mL of 25% piperidine in DMF. The suspended resin was shaken for 30 min at rt, and then the resin was washed 3× with 20 mL of DMF, 3× with 20 mL of methanol, and 3× with 20 mL of CH2Cl2. Deprotected resin (1.0 g, 0.25 mmol) was swollen in 2 mL of DMF. To the slurry was added 650 mg (1.25 mmol) of PyBOP and 217 mL (1.25 mmol) of DIEA. Separately, 443 mg (0.97 mmol) of caprolactam 23 was dissolved in 2 mL of DMF and 436 mL (2.5 mmol) of DIEA was added. The caprolactam solution was added to the resin slurry and the resin was mixed for 18 h at rt. The solvents were then removed and the coupling was repeated, with shaking at rt for 6 h. The resin was then washed 3× with 10 mL of DMF, 3× with 10 mL of methanol, and 3× with 10 mL of CH2Cl2.
  • [1750]
    Products 25 of Scheme 5: A 70 mg (17.5 mmol) portion of resin 24 was suspended in 1 mL of THF in a screw-cap vial. To the slurry was added a boronic acid (0.15 mmol), 150 mL of a 2 M solution of sodium carbonate, and 15 mg (13 mmol) of tetrakis(triphenylphosphine)palladium. The vial was tightly closed and heated to 60° C. for 16 h using a dry heater on a shaker table. The solvents were then removed by filtration and the resin was washed 3× with THF (2 mL), 3× with methanol (2 mL), 3× with water, and 3× with CH2Cl2. The resins were then placed in a glass vial and cleaved with 1 mL of 5% trifluoroacetic acid in CH2Cl2 for 30 min. The solution ws filtered off and the resin was washed with an additional 2 mL of CH2Cl2 and the combined filtrates were evaporated to dryness to yield the crude products 25. The products were purified by chromatography eluting with 10-100% ethyl acetate in hexanes to yield 13.0 to 6.0 mg (14-60%) of the final products.
  • [1751]
    Additional Examples of compounds of Formula (I) can be prepared as shown in Scheme 6. A suitable resin for solid phase synthesis such as Fmoc (Fluorenylmethylcarbonyl)-protected peptide amide linker (PAL)-derivatized polystyrene beads can be purchased from Perkin Elmer Biosystems, Inc. Deprotection of the Fmoc group under standard conditions using 20% piperidine in DMF provides the free benzylamine. Coupling of a succinic acid derivative such as 28 (which is available using chemistry outlined in Scheme 4) with a coupling agent such as HATU in a suitable solvent like DMF or N-methylpyrrolidinone provides the support-bound amide 29. The support-bound intermediate 29 can then be elaborated to biaryl structures of the type 24 using typical Suzuki coupling conditions employing a catalyst such as Palladium complexes like tetrakis(triphenylphosphine)-palladium with 2M aqueous sodium carbonate as a base in a suitable solvent like THF or DME and an excess of a boronic acid. The final compounds are liberated from the support employing 50% trifluoroacetic acid in CH2Cl2 and can be purified by conventional chromatography or preparative HPLC.
    General Procedure for Solid-Phase Synthesis According to Scheme 6
  • [1752]
    Resin 27 of Scheme 6: Fmoc-protected PAL resin 26 (0.80 g, 0.50 mmol/g, 0.40 mmol) is purchased from Advanced Chemtech and swelled in 20 ml of CH2Cl2 for 1 hour. The CH2Cl2 is removed and the resin is then treated with 25% v/v piperidine in DMF (6 mL) and allowed to shake slowly for 1 h. The solvents were removed by filtration, and the resin 27 was rinsed 3× with 20 mL of DMF, 3× with 20 mL of methanol, and 3× with 20 mL of CH2Cl2. and dried in vacuo.
  • [1753]
    Acid 28 of Scheme 6: To a solution of 0.100 g (367 mmol) of succinate 10 dissolved in 2.0 mL of dry DMF was added 0.120 mL (1.10 mmol) of N-methylmorpholine. A second solution containing 0.139 g (0.403 mmol) of caprolactam 23 of Scheme 5 dissolved in 2.0 mL of DMF was then added. To the mixed solution was added 229 mg (0.440 mmol) of PyBop and the reaction solution was stirred for 16 h at rt. The reaction solution was diluted with water (20 mL) and extracted 3× with 100 mL of ethyl acetate. The combined organic layers were dried with Na2SO4 and concentrated under reduced pressure. The resulting oil was purified by chromatography eluting with a gradient of 5-20% ethyl acetate in hexanes to provide 0.195 g (0.360 mmol, 98%) of the tert-butyl ester of Acid 28 (MS M+Na=621). The purified ester (0.195 g, 0.360 mmol) was dissolved in 10 mL of 25% trifluoroacetic acid in CH2Cl2 and stirred for 2 h at rt. The solvents were removed under reduced pressure and the acid was redissolved in 5 mL of toluene and reconcentrated 2× to remove residual TFA. The crude acid was found to be pure by 1H NMR and was used in Scheme 6 without further purification.
  • [1754]
    Resin 29 of Scheme 6. Resin 27 (800 mg, 0.40 mmol) was solvated in 4.0 mL of dry DMF and and 0.63 mL (3.6 mmol) of diisopropylethylamine was added followed by a solution of Acid 28 dissolved in 4 mL of DMF. To the slurry was then added 0.465 g (1.2 mmol) of HATU and the slurry was shaken for 26 h at rt. The solvents were removed by filtration, and the resin 29 was rinsed 3× with 20 mL of DMF, 3× with 20 mL of methanol, and 3× with 20 mL of CH2Cl2. and dried in vacuo.
  • [1755]
    Products 30 of Scheme 6: A 75 mg (0.38 mmol/g, 28.8 mmol) portion of resin 24 was suspended in 1 mL of THF in a screw-cap vial. To the slurry was added a boronic acid (0.33 mmol), 150 mL of a 2 M solution of sodium carbonate, and 15 mg (13 mmol) of tetrakis(triphenylphosphine)palladium. The vial was tightly closed and heated to 60° C. for 16 h using a dry heater on a shaker table. The solvents were then removed by filtration and the resin was washed 3× with THF (2 mL), 3× with methanol (2 mL), 3× with water, and 3× with CH2Cl2. The resins were then placed in a glass vial and cleaved with 1 mL of 5% trifluoroacetic acid in CH2Cl2 for 2 h. The solution was filtered off and the resin was washed with an additional 2 mL of CH2Cl2 and the combined filtrates were evaporated to dryness to yield the crude products 25. The products were purified by chromatography eluting with 10-100% ethyl acetate in hexanes to yield 0.5 to 2.0 mg (14-60%) of the final products.
  • [1756]
    The internal phenyl ring can be exchanged for a pyridine ring using chemistry outlined in Scheme 7. The chloromethyl pyidine 33 is prepared using a known procedure reported in Nutaitis, Charles F.; Ledeboer, Mark W. Org. Prep. Proced. Int. (1992), 24(2), 143-6 Incorporated herein by reference. After freebasing the pyridine, alkylation with the Boc-caprolactam provides pyridine intermediate 34, which can be elaborated to the protected amide 35 with succinate 10. Substitution can then be introduced using Suzuki methodology employing a palladium source such as tetrakis(triphenylphosphine)palladium(0) or bis(diphenylphosphinoferrocene)palladium(II) dichloride and a suitable base such as sodium carbonate or triethylamine in a solvent such as THF or toluene containing 10% methanol. Stille chemistry is also possible using a suitable palladium source such as tetrakis(triphenylphosphine)palladium(0) and an aryl or vinyl tin derivative in a solvent such as benzene, toluene, or xylenes. The tert-butyl ester is then deprotected under standard acidic conditions using trifluoroacetic acid and the amide is formed under standard conditions to provide products 36.
    General Procedure for Synthesis According to Scheme 7
  • [1757]
    The chloromethyl pyidine HCl salt 33 is prepared using a known procedure reported in Nutaitis, Charles F.; Ledeboer, Mark W. Org. Prep. Proced. Int. (1992), 24(2), 143-6.
  • [1758]
    Caprolactam 34: Pyridine HCl salt 33 (2.0 g, 8.3 mmol) is dissolved in 50 mL of a saturated NaHCO3 solution and the solution is extracted with 30 mL of CH2Cl2 3× followed by concentration of the organic layers to provide the free base. Separately, 1.8 g (7.8 mmol) of caprolactam 13 is dissolved in 40 mL of dry THF and chilled to −78° C. To the solution was added 8.7 mL of a 1M solution of sodium bis(trimethylsilyl)amide. The solution was brought to 0° C. and stirred for 30 min. To the resultant anion was added a solution of 1.7 g (8.3 mmol) of pyridine 33 free base dissolved in 40 mL of THF. The resulting reaction solution was stirred at rt for 18 h and then heated to 50° C. and stirred an additional 3 h. The reaction solution was allowed to cool and then 50 mL of water was added and the aqueous layer was extracted 2× with 100 mL of ethyl acteate. The combined organic layers were dried and concentrated under reduced pressure to provide the crude product which was purified by chromatography eluting with 20 to 100% ethyl acetate in hexanes to provide 1.5 g (51%) of caprolactam 34 as an oil.
  • [1759]
    Amide 35: Caprolactam 34 (0.40 g, 1.0 mmol) is dissolved in 20 mL of 50% trifluoroacetic acid in CH2Cl2 and stirred at rt for 30 min. The solvents were then removed under reduced pressure and the resulting oil was redissolved in 5 mL of toluene and reconcentrated to remove residual TFA. Separately, 0.270 g (1.0 mmol) of succinate 10 was dissolved in 5.0 mL of dry DMF and 0.44 mL (4 mmol) of N-methylmorpholine was added followed by 0.50 g (1.3 mmol) of HATU and the resulting solution was stirred at rt for 30 min. The crude deprotected caprolactam from above was dissolved in 5.0 mL of dry DMF and added to the succinate solution and the resulting solution was heated to 50° C. and stirred for 2 days. The solution was then diluted with 20 mL of water and extracted with 3 50 mL portions of ethyl acetate. The combined organic layers were dried and concentrated under reduced pressure to provide an oil which was purified by chromatography eluting with 20 to 50% ethyl acetate in hexanes to provide 0.40 g (70%) of the Amide 35.
  • [1760]
    Additional examples can be prepared by the method shown in Scheme 8. Coupling of an amine onto a commercially available aldehyde-derived resin 37 under conditions for reductive amination such as sodium tris(acetoxy)borohydride in CH2Cl2 containing 1% acetic provides a support-bound amine 38. The carboxylic acid 39 can then be coupled to the support-bound amine generating an amide 40 which can be liberated from the support employing trifluoroacetic acid in CH2Cl2.
    General Procedure for Solid-Phase Synthesis According to Scheme 8
  • [1761]
    Resin 38 of Scheme 5: Aldehyde-derived resin 37 (200 mg, 0.5 mmol/g, 0.1 mmol) is purchased from Perkin Elmer Biosystems and swelled in 3 ml of CH2Cl2 for 1 hour. An amine (1.0 mmol), sodium tris(acetoxy)borohydride (106 mg, 0.5 mmol) and acetic acid (30 uL, 1%) are added and the reaction is shaken on a shaker table for 16 h at rt. The solvents were removed by filtration and the resin 38 was rinsed 3× with 20 mL of DMF, 3× with 20 mL of methanol, and 3× with 20 mL of CH2Cl2. and dried in vacuo.
  • [1762]
    Products 40 of Scheme 8: Carboxylic acid 39 (23 mg, 0.045 mmol), diisopropylethylamine (13 mL, 0.075 mmol) and HATU (17.1 mg, 0.045 mmol) were mixed in 0.5 mL of DMF for 30 min. Amine-derived resins 38 (30 mg, 0.015 mmol) were then added and the suspension was shaken at rt for 16 h. The solvents were removed by filtration and the resins were rinsed 3× with 20 mL of DMF, 3× with 20 mL of methanol, and 3× with 20 mL of CH2Cl2. The isolated resins were then cleaved by the addition of 0.50 mL of trifluoroacetic acid. The product solutions were concentrated and redissolved in 0.5 mL of methanol and reconcentrated 2× to remove residual TFA. Product yields ranged from 0-100% based on the structure of the amine.
  • [1763]
    The compounds of Formula (I) of the present invention can also be prepared from aminolactam or aminothiolactam 42 and succinic acid derivatives 1 using amide bond syntheses known in the art, including methods commonly used in peptide syntheses, such as HATU, TBTU, BOP, pyBOP, EDC, CDI, DCC, hydroxysuccinimide, mixed carboxylic anhydride, and phenyl ester mediated couplings, as illustrated in Scheme 9 for the synthesis of aminolactam or aminothiolactam 43, an embodiment of the present invention.
    Depending on the structure of the final product, it is appreciated by those skilled in the art that protecting groups or precursor functionality convertable to the desired groups may be desireable. Protecting groups and their use in synthesis are described in Green and Wuts, Protective Groups in Organic Synthesis, (Wiley 1991). The use of protecting groups is further illustrated in Scheme 10, in which the succinate half-ester 44 (Becket et al., Synlett 1993, 137-138) is coupled to the aminobenzodiazepine 45 (Sherrill and Sugg, J. Org. Chem. 1995, 60, 730-734; Bock et al., J. Med. Chem., 1993, 36, 4276-4292) to give ester 46, followed by conversion of the ester group to the primary amide 47.
  • [1764]
    Methods for the synthesis of lactams as contemplated by the present invention in lactam ring B in Formula (I), including amino benzodiazepines, are known in the art and are disclosed in a number of references including PCT publication number WO 98/28268, which is hereby incorporated by reference. Additional references include Bock, et al, J. Org. Chem., 1987, 52, 3232-3239 and Sherrill et al, J. Org. Chem., 1995, 60, 730-734; Walsh, D. A., Synthesis, September 1980, p. 677.
  • [1765]
    The synthesis of the thiolactams of the present invention (Formula (I), A=S) can be carried out using thiolactam intermediates (42, A=S), using the methods described above. The thiolactam intermediates may be prepared from suitably protected aminolactams employing methods known to those skilled in the art, using, for example, Lawessson's reagent, P4S10, or related methods (see Taylor et al., Bioorg. Med. Chem. Lett. 1997, 7 (4), 453-456; Schwarz et al., Tetrahedron, 1997, 53 (26), 8795-8806; Achour et al., Synth. Commun. 1994, 24 (20), 2899-2905; Buege et al., Arch. Pharm. 1994, 327 (2), 99-103; Levai, et al., Arch. Pharm. 1992 (325 (11), 721-726; Duhammel et al., Tetrahedron Asymmetry 1991, 2 (3), 203-206; Bodine et al., Synth. Commun. 1982, 12, 787). Deprotection of the amine, coupling to an appropriate succinate derivative and elaboration of the distal succinic acid derivative provides the desired thiolactams of the present invention.
  • EXAMPLES
  • [1766]
    Chemical abbreviations used in the Examples are defined as follows: “DMPU” for 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone, “TBTU” for O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, and “BOP” for benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate. It is understood that one skilled in the art can discern compounds used in the synthesis of Examples of the invention may be referred to by structure and number. For example, Resin 20 refers to the resin of structure 20 in Scheme 5; succinate 9 refers to the structure 9 found in Scheme 2 which is a succinate compound.
  • [1767]
    “HPLC” is an abbreviation used herein for high pressure liquid chromatography. Reverse-phase HPLC was carried out using a Vydac C-18 column with gradient elution from 10% to 100% buffer B in buffer A (buffer A: water containing 0.1% trifluoroacetic acid, buffer B: 10% water, 90% acetonitrile containing 0.1% trifluoroacetic acid).
  • Example 1 (2R,3S) N1-[(3S)-hexahydro-1-(3,3-diphenylpropyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1768]
  • [1769]
    Step (1a): Di-tert-butyldicarbonate (10.2 g, 46.7 mmoles) was added portion wise to a solution of L-(−)-α-amino-ε-caprolactam (5.0 g, 39.0 mmoles) in dimethyl sulfoxide (30 mL). After 5 h at rt, the reaction was partitioned between water (100 mL) and ethyl acetate. The combined organic extracts were washed successively with 1 M HCl (50 mL), brine, and dried (MgSO4) and concentrated in vacuo. The residue was recrystallized in 1:1 v/v ether-hexanes, two crops yielded the desired product (6.26 g, 70%) as white solid. MS (M+H-BOC)+=129.
  • [1770]
    Step (1b): Triphenylphosphine (3.0 g, 11.4 mmoles) and carbon tetrabromide (3.75 g, 11.7 mmoles) were added successively to a cooled (0° C.) solution of 3,3-biphenyl-1-propanol (1.5 mL, 7.5 mmoles) in dichloromethane (20 mL). After 1.5 hours at rt, the mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexanes) to give the desired product (1.93 g, 93% yield) as a clear oil. MS (M-BrC2H4)+=167
  • [1771]
    Step (1c): A 1.0 M tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1.3 mL) was added over 15 minutes to compound of Step (1a) (0.29 g, 1.27 mmoles) in tetrahydrofuran (3 mL) and DMPU (2 mL) at −78° C. The iodo compound prepared from compound (1b) (0.85 g, 3.09 mmoles) by typical Finkelstein methodology, in tetrahydrofuran (4 mL) was added and the reaction was allowed to warm to rt slowly. This was stirred for 10 hours at ambient temperature, partitioned between water and ethyl acetate. The combined organic extracts were washed successively with water (20 mL), brine (20 mL), and dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by silica gel column (ethyl acetate:hexanes, 5:95 then ethyl acetate:hexanes, 15:85) to give the desired product (0.16 g, 30%). MS (M-Ot-Bu)+=349.
  • [1772]
    Step (1d): Trifluoroacetic acid (3 mL) was added to a solution of compound of Step (1c) (0.16 mg, 0.38 mmoles) in dichloromethane (9 mL). After 2 h at rt, the solvent was removed in vacuo. The residual trifluoroacetic acid was removed by azeotrope with dichloromethane (50 mL), toluene (50 mL), and dichloromethane (50 mL) successively to give the desired product (0.17 g, 99%) as a yellow oil. MS (M+H)+=323.
  • [1773]
    Step (1e): 4-Methylmorpholine (0.6 mL, 5.46 mmoles) and TBTU (0.11 g, 0.34 mmoles) were added to a solution of succinate acid (P. Becket, M. J. Crimmin, M. H. Davis, Z. Spavold, Synlett, (1993), 137-138) (0.085 g, 0.31 mmoles) in N,N-dimethylformamide (3 mL). After 30 minutes at rt, the compound from step (1d) (0.17 g, 0.39 mmoles) was added to the mixture. The reaction was stirred for 16 h at rt, then partitioned between 1 M HCl (20 mL) and ethyl acetate. The combined organic extracts were washed successively with saturated aqueous sodium bicarbonate (20 mL), water (20 mL), brine (20 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexanes, 7:93 gradient to ethyl acetate:hexanes 25:75) to give the desired product (120 mg, 67%) as a clear oil. MS (M+NH4-Ot-Bu)+=521.
  • [1774]
    Step (1f): Trifluoroacetic acid (3 mL) was added to a solution of compound of Step (1e) (120 mg, 0.21 mmoles) in dichloromethane (9 mL). After 3 hours at rt, the mixture was concentrated in vacuo. The residual trifluoroacetic acid was removed by azeotrope with toluene (1×50 mL) and dichloromethane (1×50 mL). The residue was triturated with Et2O:Hexanes 95:5, to give the desired product (75 mg, 70%) as a white solid. MS (M-H)-=519.
  • [1775]
    Step (1g): 4-Methylmorpholine (0.05 mL, 0.45 mmoles) and BOP (73 mg, 0.17 mmoles) were added to a solution of compound of Step (1f) (60 mg, 0.12 mmoles) in N,N-dimethylformamide (2 mL). Hydroxylamine (33 mg, 0.47 mmoles) was added to the mixture, the reaction was stirred for 16 h at rt, was concentrated in vacuo, was acidified with trifluoroacetic acid, then purified by reverse phase HPLC on a Vydac C-18 column, to give the desired hydroxamic acid as a white solid (45 mg, 75%). MS (M-H)=534.
  • Example 2 (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1776]
  • [1777]
    Step (2a): Triphenylphosphine (3.40 g, 13.0 mmoles) and carbontetrabromide (4.20 g, 13.0 mmoles) were added successively to a solution of m-phenoxybenzyl alcohol (1.5 mL, 8.6 mmoles). After 4 h at rt the mixture was concentrated and was purified by silica gel column (hexanes, then ethyl acetate:hexanes, 5:95) to give the desired bromide (1.3 g, 57%) as a yellow oil. MS (M-Br)+=183.
  • [1778]
    Step (2b): A 1 M solution of lithium bis(trimethylsilyl)amide was added dropwise to a solution of compound of Step (1a) (0.3 g, 1.31 mmoles) in tetrahydrofuran (5 mL) at −78° C. After 30 minutes a solution of compound of Step (2a) (0.43 g, 1.63 mmoles) in tetrahydrofuran (4 mL) was added to the mixture dropwise. The reaction was allowed to come to ambient temperature, stirred for 16 h, then partitioned between water and ethyl acetate. The combined organic extracts were washed successively with water (20 mL), brine (20 mL), dried (MgSO4) and concentrated in vacuo. The crude residue was purified by silica gel chromatography (ethyl acetate:hexanes, 5:95 then ethyl acetate:hexanes, 15:85) to give the desired product (360 mg, 67%) as a clear oil. MS (M-Ot-Bu)+=337.
  • [1779]
    Step (2c): Trifluoroacetic acid (5 mL) was added to a solution of compound of Step (2b) in dichloromethane (15 mL). After 3 h at rt the solution was concentrated in vacuo. The residual trifluoroacetic acid was removed from residue by azeotrope with toluene (50 mL) then dichloromethane (30 mL) to yield the desired amine (390 mg, 99%) as a clear oil. MS (M+H)+=311.
  • [1780]
    Step (2d): Following a procedure analogous to the preparation of Step (1e), but using the compound from of Step (2c) (390 mg, 0.88 mmoles) the amide was prepared, The crude compound was purified by silica gel chromatography to give the desired product (0.38 g, 92%) as a yellow oil. MS (M-Ot-Bu)+=491.
  • [1781]
    Step (2e): Following a procedure analogous to the preparation of step (1f), but using the compound from Step (2d) (380 mg, 0.67 mmoles), the carboxylic acid was prepared. The product was precipitated from ethyl ether with hexanes, to give the desired acid (227 mg, 66%) as a white solid. MS (M-H)-=507.
  • [1782]
    Step (2f): Following a procedure analogous to the preparation of compound of Step (1g), but using the compound from step (2e) (150 mg, 0.29 mmoles) the title compound was prepared. The crude was purified by reverse phase HPLC on a Vydac C-18 column to give the desired product (90 mg, 58%) as a white solid. MS (M-H)-=522.
  • Example 3 (2R,3S) N1-[(3S)-hexahydro-1-(phenyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1783]
  • [1784]
    Step (3a): Triethylamine (1.5 mL, 10.8 mmoles), copper (II) acetate (0.95 g, 5.2 mmoles) and phenylboric acid (1.6 g, 13.1 mmoles) were added successively to a solution of compound of Step (1a) (1.0 g, 4.4 mmoles) in dichloromethane (20 ml). After 2.5 h at rt, more phenylboric acid (0.5 g, 4.1 mmoles) was added to the mixture. After an additional 3 hours at rt more phenylboric acid (0.5 g, 4.1 mmoles) was added to the mixture. After 65 h at rt, the mixture was filtered over celite. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography (ethyl acetate:hexanes, 5:95 then 15:85) to give the desired product (250 mg, 19%). MS (M-Ot-Bu)+=231.
  • [1785]
    Step (3b): Following a procedure analogous to the preparation of compound of Step (2c), but using compound of Step (3a) (250 mg, 0.82 mmoles), the amine (300 mg, 99%) was prepared as a yellow oil. MS (M+H)+=205.
  • [1786]
    Step (3c): Following a procedure analogous to the preparation of compound of Step (1e), but using compound from Step (3b) (0.3 g, 0.94 mmoles), the amide was prepared. The residue was purified by silica gel chromatography (ethyl acetate:hexanes, 5:95 to 20:80 in 5% increments, 500 mL each ratio) to give the desired product (210 mg, 60%) as a clear oil. MS (M+H-t-Bu)+=403.
  • [1787]
    Step (3d): Following a procedure analogous to the preparation of compound of Step (1f), but using compound from sStep (3c) (200 mg, 0.44 mmoles) the acid was prepared. The crude oil was triturated with ether:hexanes 1:1 to give the desired acid (114 mg, 65%) as a white solid. MS (M-OH)+=385.
  • [1788]
    Step (3e): Following a procedure analogous to the preparation of compound of Step (1g), but using compound from Step (3d) (82 mg, 0.20 mmoles) the title compound was prepared. The crude product was purified by reverse phase HPLC on a Vydac C-18 column to give the desired product (80 mg, 94%). MS (M-H)=416.
  • Example 4 (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(methyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1789]
  • [1790]
    Following a procedure analogous to the preparation of Example 3, compound of Step (2e) (100 mg, 0.20 mmol) was treated with HATU (O-(7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate) (114 mg, 0.30 mmol) and N-methyl morpholine (66 mL, 0.6 mmol) in 2 mL of DMF for 15 min at rt. A solution of 2.0 M methylamine in THF (0.2 mL, 0.4 mmol) was added and the reaction solution was stirred for 1 h at rt. The reaction solution was diluted with 1N HCl (5 mL) and extracted 3× with 10 mL of ethyl acetate. The combined organic layers were washed with a saturated sodium bicarbonate solution (5 mL) and brine (5 mL), dried over magnesium sulfate, and concentrated in vacou to provide the crude amide. Purification by reverse phase HPLC on a Vydac-18 column provided the desired amide (30 mg, 30%). MS (M+Na)+=544.
  • Example 5 (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(methoxy)-N-4-(methyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1791]
  • [1792]
    Following a procedure analogous to the preparation of Example 4, compound of Step (2e) (100 mg, 0.20 mmol) was activated and condensed with N,O-dimethylhydroxylamine hydrochloride (40 mg, 0.40 mmol). Purification by reverse phase HPLC on a Vydac-18 column provided the desired amide (30 mg, 30%). MS (M+Na)+=574.
  • Example 6 (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(methoxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1793]
  • [1794]
    Following a procedure analogous to the preparation of Example 4, compound of Step (2e) (100 mg, 0.20 mmol) was activated and condensed with O-methylhydroxylamine hydrochloride (40 mg, 0.40 mmol). Purification by reverse phase HPLC on a Vydac-18 column provided the desired amide (30 mg, 30%). MS (M+Na)+=560.
  • Example 7 (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1795]
  • [1796]
    Following a procedure analogous to the preparation of Example 4, compound of Step (2e) (100 mg, 0.20 mmol) was activated and condensed with a 2.0 M solution of ammonia in dioxane (0.2 mL, 0.4 mmol). Purification by reverse phase HPLC on a Vydac-18 column provided the desired amide (30 mg, 30%). MS (M+Na)+=530.
  • Example 7A (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(amino)-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1797]
  • [1798]
    Following a procedure analogous to the preparation of Example 4, compound of Step (2e) (100 mg, 0.20 mmol) was activated and condensed with hydrazine (13 mg, 0.4 mmol). Purification by reverse phase HPLC on a Vydac-18 column provided the desired amide (11.1 mg, 21%). MS (M+Na)+=542.
  • Example 8 (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1799]
  • [1800]
    (8a) Compound 8a was synthesized following a procedure analogous to the preparation of the compound 1e, but using the caprolactam 2c (2.5 g, 5.89 mmol), succinate 9 (1.64 g, 6.0 mmol), and HATU instead of TBTU. The compound was purified by chromatogrphy eluting with 5% methanol in CH2Cl2 to afford 1.50 g (45%) of the desired ester.
  • [1801]
    (8b) The ester from 8a (1.18 g, 2.10 mmol) was dissolved in 10 mL of a 50% solution of trifluoroacetic acid in CH2Cl2 and stirred at rt for 2 h. The solvents were removed by concentration under reduced pressure and the crude product was dissolved in 10 mL of toluene and reconcentrated twice to remove residual TFA. The crude acid was used without further purification or characterization.
  • [1802]
    Following a procedure analogous to the preparation of Example 7, compound 8b (1.065 g, 2.10 mmol) was activated and condensed with an excess of gaseous ammonia. Purification by reverse phase HPLC on a Vydac-18 column provided 500 mg (47%) of the desired compound of Example 8. MS (M+Na)+=528.
  • Example 9 (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(allyl)-butanediamide
  • [1803]
  • [1804]
    Example 9 was synthesized following a procedure analogous to the preparation of Example 2, but using succinate 9 (Scheme 2). Purification by reverse phase HPLC on a Vydac-18 column provided 150 mg of Example 9. MS (M+Na)+=544.
  • Example 10 (2R,3S) N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1805]
  • [1806]
    The general procedure reported for Scheme 5 was followed using 2,4-dichlorophenyl boronic acid. Purification afforded 6.0 mg (60%) of the desired product. MS (M+Na)+=598.
  • Example 11 (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1807]
  • [1808]
    The general procedure reported for Scheme 5 was followed using 4-fluorophenyl boronic acid. Purification afforded 5.0 mg (54%) of the desired product. MS (M+Na)+=548.
  • Example 12 (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1809]
  • [1810]
    The general procedure reported for Scheme 5 was followed using 4-methylphenyl boronic acid. Purification afforded 3.0 mg (33%) of the desired product. MS (M+Na)+=544.
  • Example 13 (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1811]
  • [1812]
    The general procedure reported for Scheme 5 was followed using 4-methoxyphenyl boronic acid. Purification afforded 3.0 mg (32%) of the desired product. MS (M+Na)+=560.
  • Example 14 (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1813]
  • [1814]
    The general procedure reported for Scheme 5 was followed using 3-methylphenyl boronic acid. Purification afforded 3.0 mg (33%) of the desired product. MS (M+Na)+=544.
  • Example 15 (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1815]
  • [1816]
    The general procedure reported for Scheme 5 was followed using 3-chloro-4-fluorophenyl boronic acid. Purification afforded 4.0 mg (41%) of the desired product. MS (M+Na)+=582.
  • Example 16 (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1817]
  • [1818]
    The general procedure reported for Scheme 5 was followed using 4-trifluoromethylphenyl boronic acid. Purification afforded 4.0 mg (40%) of the desired product. MS (M+Na)+=598.
  • Example 17 (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1819]
  • [1820]
    The general procedure reported for Scheme 5 was followed using 3-methoxyphenyl boronic acid. Purification afforded 4.1 mg (44%) of the desired product. MS (M+Na)+=560.
  • Example 18 (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1821]
  • [1822]
    The general procedure reported for Scheme 5 was followed using 3-fluorophenyl boronic acid. Purification afforded 3.5 mg (38%) of the desired product. MS (M+Na)+=548.
  • Example 19 (2R,3S) N1-[(3S)-hexahydro-1-(3-(2-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1823]
  • [1824]
    The general procedure reported for Scheme 5 was followed using 2-methoxyphenyl boronic acid. Purification afforded 1.3 mg (14%) of the desired product. MS (M+Na)+=560.
  • Example 20 (2R,3S) N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1825]
  • [1826]
    The general procedure reported for Scheme 5 was followed using 2-naphthyl boronic acid. Purification afforded 3.0 mg (31%) of the desired product. MS (M+Na)+=580.
  • [1827]
    It will be understood by one skilled in the art that Scheme 6 can be followed in a manner analogous to the procedure for Scheme 5.
  • Example 21 (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1828]
  • [1829]
    The general procedure reported for Scheme 6 was followed using 4-methoxyphenyl boronic acid. Purification afforded 0.5 mg of the desired product. MS (M+Na)+=544.
  • Example 22 (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1830]
  • [1831]
    The general procedure reported for Scheme 6 was followed using 3-fluorophenyl boronic acid. Purification afforded 1.6 mg of the desired product. MS (M+Na)+=532.
  • Example 23 (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1832]
  • [1833]
    The general procedure reported for Scheme 6 was followed using 4-trifluoromethylphenyl boronic acid. Purification afforded 0.7 mg (4.3%) of the desired product. MS (M+Na)+=582.
  • Example 24 (2R,3S) N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1834]
  • [1835]
    The general procedure reported for Scheme 6 was followed using 2,6-dichlorophenyl boronic acid. Purification afforded 1.8 mg (11%) of the desired product. MS (M+Na)+=582.
  • Example 25 (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1836]
  • [1837]
    The general procedure reported for Scheme 6 was followed using 4-tolyl boronic acid. Purification afforded 1.8 mg (12%) of the desired product. MS (M+Na)+=528.
  • Example 26 (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1838]
  • [1839]
    The general procedure reported for Scheme 6 was followed using 4-methoxyphenyl boronic acid. Purification afforded 0.5 mg (3.3%) of the desired product. MS (M+Na)+=544.
  • Example 27 (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1840]
  • [1841]
    The general procedure reported for Scheme 6 was followed using 4-fluoro-3-chlorophenyl boronic acid. Purification afforded 0.5 mg (3.3%) of the desired product. MS (M+Na)+=567.
  • Example 28 (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1842]
  • [1843]
    The general procedure reported for Scheme 6 was followed using 2-methoxyphenyl boronic acid. Purification afforded 0.8 mg (5.3%) of the desired product. MS (M+Na)+=544.
  • Example 29 (2R,3S) N1-[(3S)-hexahydro-1-(3-(2-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1844]
  • [1845]
    The general procedure reported for Scheme 6 was followed using 2-methoxyphenyl boronic acid. Purification afforded 1.5 mg (10%) of the desired product. MS (M+Na)+=544.
  • [1846]
    It will be understood by one skilled in the art that Scheme 7 can be followed in a manner analogous to the procedure for Schemes 5 and 6.
  • Example 30 (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)pyrid-5-ylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1847]
  • [1848]
    Amide 35 of Scheme 7 (0.10 g, 0.18 mmol) was dissolved in 5 mL of toluene and 41 mg (0.27 mmol) of 4-methoxyphenyl boronic acid was added, followed by 31 mg (0.0147 mmol) of tetrakis(triphenylphosphine)palladium, 0.5 mL of a 2M odium cabonate solution and 0.5 mL of methanol. The reaction solution was heated to reflux for 16 h and then allowed to cool to rt. The reaction solution was diluted with 10 mL of water and extracted 2× with 50 mL of ethyl acetate. The combined organic layers were dried and concentrated and the resulting oil was purified by chromatography eluting with 30 to 100% ethyl acetate in hexanes as a solvent to provide 30 mg (29%) of biaryl product. MS (M+H)+=580.
  • [1849]
    The purified biaryl product was dissolved in 10 mL of 1:1 trifluoroacetic acid/CH2Cl2 and stirred at rt for 2 h. The solvents were then removed under reduced pressure and the resulting oil was redissolved in 5 mL of toluene and reconcentrated to remove residual TFA. The crude acid (25 mg, 0.047 mmol) was then dissolved in 1 mL of DMF and 10 mL of N-methylmorpholine (0.094 mmol) and 42 mg (0.062 mmol) HATU were added and the reaction solution was stirred at rt for 45 min. Gaseous ammonia was then bubbled in at a gentle rate for about 1 minute and the solution was stirred for an additional 1 min. The reaction solution was then diluted with 10 mL of water and extracted 3× with 30 mL of ethyl acetate. The combined organic layers were dried and concentrated under reduced pressure to a solid which was purified by reversed phase HPLC to provide 3.5 mg (10%) of the compound of Example 30 as its trifluoroacetic acid salt. MS (M+H)+=523.
  • Example 31 (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)pyrid-5-ylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1850]
  • [1851]
    The general procedure reported for the compound of Example 30 was followed using 4-trifluoromethylphenyl boronic acid. Purification by HPLC afforded 6.0 mg of the desired product from as its trifluoroacetic acid salt. MS (M+Na)+=583.
  • Example 32 (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)pyrid-5-ylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1852]
  • [1853]
    Amide 35 (0.30 g, 0.54 mmol) was dissolved in 3 mL of DMF and 123 mg (0.70 mmol) of 4-methoxyphenyl boronic acid was added, followed by 44 mg (0.0543 mmol) of bis(diphenylphosphinoferrocene)palladim (II) dichloride and 1.0 mL (7.18 mmol) of triethylamine. The reaction solution was heated to 80° C. for 24 h and then allowed to cool to rt. The reaction solution was diluted with 10 mL of water and extracted 2× with 50 mL of ethyl acetate. The combined organic layers were dried and concentrated and the resulting oil was purified by chromatography eluting with 20 to 100% ethyl acetate in hexanes as a solvent to provide 140 mg (50%) of biaryl product. MS (M+Na)+=624.
  • [1854]
    The general procedure reported for the compound of Example 30 was then followed to provide the amide. Purification by chromatography eluting with 20 to 100% ethyl acetate in hexanes afforded 45 mg of the desired product of Example 32 as its trifluoroacetic acid salt. MS (M+Na)+=567.
  • Example 33 (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(butyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1855]
  • [1856]
    The general procedure reported for Scheme 8 was followed using butylamine. Analysis by 1HNMR integration relative to an internal standard revealed a yield of 100% of the desired product. MS (M+Na)+=586.
  • Example 34 (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(2-furylmethyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1857]
  • [1858]
    The general procedure reported for Scheme 8 was followed using 2-furylmethylamine. Analysis by 1HNMR integration relative to an internal standard revealed a yield of 75% of the desired product. MS (M+Na)+=610.
  • Example 35 (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(cyclopentyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1859]
  • [1860]
    The general procedure reported for Scheme 8 was followed using cyclopentylamine. Analysis by 1HNMR integration relative to an internal standard revealed a yield of 42% of the desired product. MS (M+Na)+=598.
  • Example 36 (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(cinnamyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1861]
  • [1862]
    The general procedure reported for Scheme 8 was followed using cinnamylamine. Analysis by 1HNMR integration relative to an internal standard revealed a yield of 100% of the desired product. MS (M+Na)+=646.
  • Example 37 (2R,3S) N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide
  • [1863]
  • [1864]
    3-Bromomethylbenzophenone. A solution of 3-methylbenzophenone (20 g, 102 mmol) dissolved in 40 mL of 1,2-dibromoethane was heated to reflux. Over a period of about 3 hours a solution of 105 mmol of bromine dissolved in 6 mL of 1,2-dibromoethane was added to the refluxing solution. After the addition was complete the solution was allowed to cool to rt and diluted with 100 mL of dichloromethane. The organic layer was extracted with 1×25 mL of 1 N HCl, 2×15 mL of NaHCO3 Solution, and 2×25 ML of brine. The organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was then distilled to afford the product, 16.5 g (60%) as an oil that solidified upon standing, b.p. 160° C. at 300 mTorr. 1H NMR analysis shows that the product contains approximately 7% of the dibromide.
  • [1865]
    3-(1,1-dimethylethylcarbmethoxy-N-(benzophenone-3-yl-methyl)caprolactam. Diisopropylamine (4.2 mL, 30 mmol) was dissolved in 25 mL of THF and chilled to −78° C. To the solution was added 10 mL of 2.5M n-butyllithium in hexanes and the solution was warmed to 0° C. and allowed to stir for 10 min. A solution of Boc-protected aminocaprolactam 1a (5.0 grams, 22 mmol) dissolved in 25 mL of THF was then added and the reaction solution was stirred for 1 h at 0° C. Solid 3-bromomethyl-benzophenone was then added and the reaction solution was allowed to warm to rt and stir overnight. The reaction solution was diluted with water and extracted into ethyl acetate (100 mL). The organic layer was rinsed with 2×25 mL of 1 N HCl, 2×25 mL of saturated NaHCO3 and 2×25 mL of brine, dried over magnesium sulfate, and dried in vacuo. Chromatography eluting with a gradient of 30% to 40% ethyl acetate in hexanes afforded the pure benzophenone-substituted caprolactam derivative (7.4 g, 80%). MS (M+Na)+=445.
  • [1866]
    The compound of Example 10 was synthesized in a manner analagous to the synthesis of the compound of Example 8 using succinate 9 and the benzophenone-substituted caprolactam derivative. The compound was purified by crystallization from ethyl acetate to afford 0.26 g of crystals. MS (M+Na)+=540.
  • Example 38 (2R,3S) N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1867]
  • [1868]
    The compound of Example 11 was synthesized in a manner analagous to the synthesis of the compound of Example 8 using succinate 10 and the benzophenone-substituted caprolactam derivative. The compound was purified by crystallization from ethyl acetate to afford 0.25 g of crystals. MS (M+Na)+=542.
  • Example 39 (2R,3S) N1-[(3S)-hexahydro-1-(4-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide
  • [1869]
  • [1870]
    (39-a) 3-(1,1-dimethylethylcarbomethoxy-N-(4-bromophenylmethyl)caprolactam. The title compound was synthesized in a manner analogous to the preparation of 3-(1,1-dimethylethylcarbomethoxy-N-(benzophenone-3-yl-methyl)caprolactam in Example 10 but using 4-bromobenzyl bromide as the alkylaing agent. The compound was purified by chromatography eluting with 5-20% ethyl acetate in hexanes as eluent to provide 7.0 g (70%) of the title compound as a solid. MS (M+Na)+=419.
  • [1871]
    (39-b) 3-(1,1-dimethylethylcarbomethoxy-N-(4,-(4′-trifluoromethylphenyl)phenylmethyl)caprolactam. To a solution of 3-(1,1-dimethylethylcarbomethoxy-N-(4-bromophenylmethyl)caprolactam (0.5 g, 1.26 mmol) dissolved in 10 mL of toluene was added 263 mg (1.38 mmol) of 4-trifluoromethylphenyl boronic acid, 1 mL of methanol, and 1 mL of a 2M solution of potassium carbonate. The solution was degassed by nitrogen bubbling for 5 min, and then 33 mg of tris(dibenzylideneacetone)dipalladium (0) chloroform adduct and 66 mg of triphenylphosphine was added. The solution ws heated to reflux for 16 h and then allowed to cool and diluted with 20 mL of water. The aqueous layer was extracted 3× with 25 mL of ethyla acetate and concentrated. The resulting oil was purified by chromatography eluting with 20% ethyl acetate in hexanes to afford 0.47 g (81%) of an oil which crystallized on standing.
  • [1872]
    (39-d) The compound 39-d was synthesized in a manner analagous to the synthesis of the compound of Example 8 using succinate 10 (280 mg, 1.04 mmol) and 3-(1,1-dimethylethylcarbomethoxy-N-(4,-(4′-trifluoromethylphenyl)-phenylmethyl)caprolactam. The compound was purified by chromatography eluting with 20-100% ethyl acetate in hexanes to afford 40 mg of a white powder. MS (M+H)+=560.
  • Example 40 (2S,3R) N1-[(3S)-hexahydro-1-(3-(2-tetrazolylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(propyl)-3-(2-methylpropyl)-butanediamide
  • [1873]
  • [1874]
    (40-a) The compound of Example 40 was synthesized in a manner analogous to the synthesis of the compound of Example 39, but using the substituted acid 28 of Scheme 6 (50 mg, 0.10 mmol) and o-((N-trityl)-tetrazole)phenylboronic acid under the conditions for the formation of the compound (39-b). The desired biaryl acid was isolated as an impure mixture (134 mg) and used directly in the next step.
  • [1875]
    (40-b) The acid 40-a (134 mg, impure mixture) was converted to the amide under the conditions reported for the compound of Example 8. The crude amide was then dissolved in 2 mL of 10% trifluoroacetic acid in methanol and allowed to stir at rt for 30 min. The solvents were removed and the residue was purified by chromatography eluting with 10% methanol in ethyl acetate to provide 40 mg (71%, 2 steps) of the compound of Example 40 as a sticky powder. MS (M+Na)+=582.
  • Example 41 (2S,3R) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(propyl)-3-(2-methylpropyl)-butanediamide
  • [1876]
  • [1877]
    (41-a) The compound of Example 41 is formed by coupling Succinate 23 (480 mg, 1.21 mmol) with the substituted caprolactam TFA salt 2c under the conditions reported for the synthesis of the compound of Example 8. The crude fluorenylmethyl ester was used in the next step with out further purification. MS (M+Na)+=709.
  • [1878]
    (41-b) The crude fluorenylmethyl ester is dissolved in 2 mL of a 50% solution of piperidine in CH2Cl2 and stirred for 3 h at rt. A 10 mL portion of 1N HCl was then added and the mixture was extracted 3× with 10 mL of ethyl acetate. The crude acid was used in the next step with out further purification. MS (M+H)+=509.
  • [1879]
    The compound of Example 41 was then prepared using the acid 41-b under the conditions reported for compound of Example 28. The compound was purified by chromatography eluting with 5% methanol in CH2Cl2 to afford 120 mg (19%, 3 steps) of a white powder. MS (M+H)+=508.
  • Example 42 (2S,3R) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide
  • [1880]
  • [1881]
    3-Phenoxybenzyl iodide: To a solution of 3-phenoxybenzyl chloride (10.0 g, 45.7 mmol) in 200 ml acetone was added sodium iodide (7.6 g, 507 mmol). The mixture was stirred at temperature overnight. The mixture was diluted with 300 ml hexane and the organic layer was washed twice with 5% sodium bicarbonate, once with brine and then dried over MgSO4. Evaporation of the filtrate gave a light yellow oil. The product was used in next step without purification. 1H NMR (CDCl3) 4.4 (s,2H), 6.8-7.4 (m, 9H).
  • [1882]
    Synthesis of Example 42:
  • [1883]
    To a solution of benzodiazepine 50 (910 mg, 3.63 mmol), succinate 2 (980 mg, 3.63 mmol), hydroxybenzotriazole (980 mg., 7.25 mmol) and EDC (870 mg, 4.54 mmol) in 100 ml CH2Cl2 at 0 degrees was added triethylamine (0.76 ml, 5.45 mmol). The reaction mixture was washed with saturated sodium bicarbonate solution, 1.0N HCl, brine and dried over MgSO4. Evaporation of the organic layer and purification by column chromatography on silica gel with hexane-ethyl acetate (7:3) gave 610 mg of benzodiazepine 51 as a white solid. M+H=504.37. 1H NMR (CDCl3) 0.8-1.0 (m, 6H), 1.0-1.2 (m, 1H), 1.4-1.5 (d, 9H), 1.6-1.9 (m, 2H), 2.2-2.8 (m, 4H), 4.9-5.2 (m, 2H), 5.6 (dd, 1H), 5.6-6.0 (m, 1H), 7.0-7.6 (m, 9H).
  • [1884]
    To a solution of benzodiazepine 5 (440 mg, 0.875 mmol) in DMF (20 ml) at 0 degrees was added NaH (45 mg, 1.12 mmol). The mixture was stirred at 0 degrees for 1.5 hr and then a solution of 3-phenoxylbenzyl iodide (330 mg, 1.06 mmol) in 10 ml DMF was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. TLC using hexanes:EtOAc 6:4 (product Rf=0.31) indicated that the reaction was complete. The reaction mixture was quenched with water, and the solvent was evaporated under high vacuum, which provided a viscous yellow oil. The product benzodiazepine 52 was dissolved in ethyl acetate, which was washed with water (2×), brine and then dried over MgSO4.
  • [1885]
    Evaporation of solvent gave 600 mg of benzodiazepine 52 as a yellow oil which was not further purified. M+H=686.3, M+Na=708.3. 1H NMR (CDCl3) 0.8-1.0 (m, 6H), 1.0-1.3 (m, 1H), 1.4-1.5 (d, 9H), 1.5-1.9 (2H), 2.2-2.7 (4H), 4.6-4.8 (d,1H), 4.9-5.2 (m, 2H), 5.6-5.9 (m, 3H), 6.6-7.6 (m, 18H).
  • [1886]
    A solution of benzodiazepine 52 in 40 ml of TFA/CH2Cl2 (1:1) was stirred overnight at room temperature then evaporated to dryness. Repeated addition of toluene and evaporation provided 560 mg. of 53 as a yellow solid. (M−H=629.1)
  • [1887]
    To a solution of benzodiazepine 53 and HATU (410 mg, 1.08 mmol) in 30 ml DMF was added diisopropylethylamine (0.6 ml, 3.44 mmol) at 0 degrees. After 10 minutes, ammonia gas was bubbled through the solution for two minutes, and the reaction mixture was allowed to warm to room temperature and stirred overnight. Addition of water and solvent evaporation under high vacuum provided a yellow solid. The solid was taken up in ethyl acetate-water (1:1), and the organic layer was washed with water (2×), brine and then dried over MgSO4. Evaporation of solvent gave a light yellow solid. Chromatographic purification on silica gel using CH2Cl2:methanol (10:0.5) gave 256 mg of Example 42. M+H=629.2 HNMR (CDCl3) 0.8-1.0 (m, 6H), 1.2-1.4 (m, 1H), 1.6-2.0 (m, 2H), 2.2-2.8(4H), 4.6-4.8 (m, 1H), 5.0-5.2(m, 2H), 5.6-5.9 (m, 3H), 6.2-7.8 (m, 18H).
  • Example 43 (2R) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-butanediamide
  • [1888]
  • [1889]
    Step (43a): The compound of Step (43a) is formed by coupling succinate 7 (115 mg, 0.5 mmol) with the substituted caprolactam TFA salt (212 mg, 0.5 mmol) from Step (2c) of Example 2 under the conditions reported for the synthesis of the compound of Example 8. The crude tert-butyl ester was taken on without further purification.
  • [1890]
    Step (43b): The compound of Step (43b) is formed by dissolving the crude product from Step (43a) in 5 mL of a 1:1 solution of TFA/CH2Cl2 and stirring at room temperature for 2 hours. Concentration followed by reconcentration twice from 10 mL of toluene provides the crude acid which was taken on with no further purification.
  • [1891]
    Step (43c): The title compound, Example 43, was prepared using the acid from Step (43b) under the conditions reported for the compound of Example 7. The compound was purified by chromatography eluting with 5% methanol in CH2Cl2 to afford 50 mg (21%, 3 steps) of a white powder. MS (M+Na)+=488.
  • Utility
  • [1892]
    Aβ production has been implicated in the pathology of Alzheimer's Disease (AD). The compounds of the present invention have utility for the prevention and treatment of AD by inhibiting Aβ production. Methods of treatment target formation of Aβ production through the enzymes involved in the proteolytic processing of β-amyloid precursor protein. Compounds that inhibit b or g secretase activity, either directly or indirectly, control the production of Aβ. Such inhibition of β or γ secretases reduces production of Aβ, and is expected to reduce or prevent the neurological disorders associated with Aβ protein, such as Alzheimer's Disease.
  • [1893]
    Cellular screening methods for inhibitors of Aβ production, testing methods for the in vivo suppression of Aβ production, and assays for the detection of secretase activity are known in the art and have been disclosed in numerous publications, including PCT publication number WO 98/22493, EPO publication number 0652009, U.S. Pat. No. 5,703,129 and U.S. Pat. No. 5,593,846; all hereby incorporated by reference.
  • [1894]
    The compounds of the present invention have utility for the prevention and treatment of disorders involving Aβ production, such as cerebrovascular disorders.
  • [1895]
    Compounds of the present invention have been shown to inhibit Aβ production, as determined by the secretase inhibition assay described below.
  • [1896]
    Compounds of the present invention have been shown to inhibit Aβ production, utilizing the C-terminus b amyloid precursor protein accumulation assay described below.
  • [1897]
    Compounds of Formula (I) are expected to possess γ-secretase inhibitory activity. The γ-secretase inhibitory activity of the compounds of the present invention is demonstrated using assays for such activity, for Example, using the assay described below. Compounds of the present invention have been shown to inhibit the activity of γ-secretase, as determined by the Aβ immunoprecipitation assay.
  • [1898]
    Compounds provided by this invention should also be useful as standards and reagents in determining the ability of a potential pharmaceutical to inhibit Aβ production. These would be provided in commercial kits comprising a compound of this invention.
  • [1899]
    As used herein “μg” denotes microgram, “mg” denotes milligram, “g” denotes gram, “μL” denotes microliter, “mL” denotes milliliter, “L” denotes liter, “nM” denotes nanomolar, “μM” denotes micromolar, “mM” denotes millimolar, “M” denotes molar, “nm” denotes nanometer, “SDS” denotes sodium dodecyl sulfate, and “DMSO” denotes dimethyl sulfoxide, and “EDTA” denotes ethylenediaminetetraacetato.
  • [1900]
    A compound is considered to be active if it has an IC50 or Ki value of less than about 100 μM for the inhibition of Aβ production or inhibition of proteolytic activity leading to Aβ production. Compounds, as demonstrated by use of the invention, have demonstrated IC50 values, for the inhibition of Aβ production, of less than about 100 μM. Preferably compounds, as demonstrated by use of the invention, demonstrate IC50 values, for the inhibition of Aβ production, of less than about 1 μM. More preferably compounds, as demonstrated by use of the invention, demonstrate IC50 values, for the inhibition of Aβ production, of less than about 100 nM. Even more preferably compounds, as demonstrated by use of the invention, demonstrate IC50 values, for the inhibition of Aβ production, of less than about 50 nM.
  • [0000]
    β Amyloid Precursor Protein Accumulation Assay (βAPPA Assay)
  • [1901]
    An assay to evaluate the accumulation of Aβ protein was developed to detect potential inhibitors of secretases. The assay uses the N 9 cell line, characterized for expression of exogenous APP by immunoblotting and immunoprecipitation.
  • [1902]
    The effect of test compounds on the accumulation of Aβ in the conditioned medium is tested by immunoprecipitation. N 9 cells are grown to confluency in 6-well plates and washed twice with 1×Hank's buffered salt solution. The cells are starved in methionine/cysteine deficient media for 30 min., followed by replacement with fresh deficient media containing 150 uCi Tran35S-LABEL™ (ICN). Test compounds dissolved in DMSO (final concentration 1%) are added, over a range of 1 picomolar to 100 micromolar, together with the addition of the fresh media containing Tran35S-LABEL™. The cells are incubated for 4 h at 37° C. in a tissue culture incubator.
  • [1903]
    At the end of the incubation period, the conditioned medium is harvested and pre-cleared by the addition of 5 μl normal mouse serum and 50 ul of protein A Sepharose (Pharmacia), mixed by end-over-end rotation for 30 minutes at 4° C., followed by a brief centrifugation in a microfuge. The supernatant is then harvested and transferred to fresh tubes containing 5 ug of a monoclonal antibody (examples of antibodies include but are not limited by, clone 1101.1, directed against an internal peptide sequence in Aβ; or 6E10 from Senetek; or 4G8 from Senetek; additionally polyclonals from rabbit antihuman Aβ from Boehringer Mannheim) and 50 μl protein A Sepharose. After incubation overnight at 4° C., the samples are washed three times with high salt washing buffer (50 mM Tris, pH 7.5, 500 mM NaCl, 5 mM EDTA, 0.5% Nonidet P-40), three times with low salt wash buffer (50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM EDTA, 0.5% Nonidet P-40), and three times with 10 mM Tris, pH 7.5. The pellet after the last wash is resuspended in SDS sample buffer (Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriphage T4. Nature 227, 680-5, 1970.) and boiled for 3 minutes. The supernatant is then fractionated on either 10-20% Tris/Tricine SDS gels or on 16.5% Tris/Tricine SDS gels. The gels are dried and exposed to X-ray film or analyzed by phosphorimaging. The resulting image is analyzed for the presence of Aβ polypeptides. The steady-state level of Aβ in the presence of a test compound is compared to wells treated with DMSO (1%) alone. A typical test compound in this assay blocks Aβ accumulation in the conditioned medium, and is considered active with an IC50 less than 100 μM.
  • [0000]
    C-Terminus β-Amyloid Precursor Protein Accumulation Assay (CTF Assay)
  • [1904]
    The effect of test compounds on the accumulation of C-terminal fragments is determined by immunoprecipitation of APP and fragments thereof from cell lysates. N 9 cells are metabolically labeled, as above, with media containing Tran35S-LABEL™, in the presence or absence of test compounds. At the end of the incubation period, the conditioned medium are harvested and cells lysed in RIPA buffer (10 mM Tris, pH 8.0 containing 1% Triton X-100, 1% deoxycholate, 0.1% SDS, 150 mM NaCl, 0.125% NaN3). Again, lysates are precleared with 5 ul normal rabbit serum/50 ul protein A Sepharose, followed by the addition of BC-1 antiserum (15 μl;) and 501 μl protein A Sepharose for 16 hours at 4° C. The immunoprecipitates are washed as above, bound proteins eluted by boiling in SDS sample buffer and fractionated by Tris/Tricine SDS-PAGE. After exposure to X-ray film or phosphorimager, the resulting images are analyzed for the presence of C-terminal APP fragments. The steady-state level of C-terminal APP fragments is compared to wells treated with DMSO (1%) alone. A typical test compound in this assay stimulates C-terminal fragment accumulation in the cell lysates, and is considered active with an IC50 less than 100 μM.
  • [0000]
    Accumulation-Release Assay
  • [1905]
    This immunoprecipitation assay is specific for g secretase activity (i.e., proteolytic activity required to generate the C-terminal end of Aβ either by direct cleavage or generating a C-terminal extended species which is subsequently further proteolyzed). N 9 cells are pulse labeled with media containing Tran35S-LABEL™ in the presence of a reported g secretase inhibitor (MDL 28170; Higaki J, Quon D, Zhong Z, Cordell B. Inhibition of beta-amyloid formation identifies proteolytic precursors and subcellular site of catabolism. Neuron 14, 651-659, 1995) for 1 h, followed by washing to remove 35S radiolabel and MDL 28170. The media is replaced and test compounds are added over a dose range (for example 0.1 nM to 100 uM). The cells are chased for increasing periods of times and Aβ is isolated from the conditioned medium and C-terminal fragments from cell lysates (see accumulation assay above). The activity of test compounds are characterized by whether a stabilization of C-terminal fragments is observed and whether Aβ is generated from these accumulated precursor. A typical test compound in this assay prevents the generation of Aβ out of accumulated C-terminal fragments and is considered active with an IC50 less than 100 μM.
  • Dosage and Formulation
  • [1906]
    The compounds determined from the present invention can be administered orally using any pharmaceutically acceptable dosage form known in the art for such administration. The active ingredient can be supplied in solid dosage forms such as dry powders, granules, tablets or capsules, or in liquid dosage forms, such as syrups or aqueous suspensions. The active ingredient can be administered alone, but is generally administered with a pharmaceutical carrier. A valuable treatise with respect to pharmaceutical dosage forms is Remington's Pharmaceutical Sciences, Mack Publishing.
  • [1907]
    The compounds determined from the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, they may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed to prevent or treat neurological disorders related to β-amyloid production or accumulation, such as Alzheimer's disease and Down's Syndrome.
  • [1908]
    The compounds of this invention can be administered by any means that produces contact of the active agent with the agent's site of action in the body of a host, such as a human or a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • [1909]
    The dosage regimen for the compounds determined from the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
  • [1910]
    Advantageously, compounds determined from the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
  • [1911]
    The compounds identified using the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches wall known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • [1912]
    In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as carrier materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • [1913]
    For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • [1914]
    The compounds determined from the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • [1915]
    Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds determined from the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
  • [1916]
    Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • [1917]
    Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
  • [1918]
    Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
  • [1919]
    The Tables below provide representative Examples of compounds of Formula (I) of the present invention.
    TABLE 3
    Ex # R1 R2 R3 Z—Y—X—W
     1 H OH propyl 3,3-diphenylpropyl
     2 H OH propyl 3-phenoxybenzyl
     3 H OH propyl phenyl
     4 H CH3 propyl 3-phenoxybenzyl
     5 CH3 OCH3 propyl 3-phenoxybenzyl
     6 H OCH3 propyl 3-phenoxybenzyl
     7 H H propyl 3-phenoxybenzyl
      7A H NH2 propyl 3-phenoxybenzyl
     8 H H allyl 3-phenoxybenzyl
     9 H OH allyl 3-phenoxybenzyl
    10 H OH propyl 3-(2,4-dichlorophenyl)-
    benzyl
    11 H OH propyl 3-(4-fluorophenyl)-benzyl
    12 H OH propyl 3-(4-methylphenyl)-benzyl
    13 H OH propyl 3-(4-methoxyphenyl)-benzyl
    14 H OH propyl 3-(3-methylphenyl)-benzyl
    15 H OH propyl 3-(3-chloro-4-
    fluorophenyl)-benzyl
    16 H OH propyl 3-(4-trifluoromethyl-
    phenyl)benzyl
    17 H OH propyl 3-(3-methophenyl)-benzyl
    18 H OH propyl 3-(3-fluorophenyl)-benzyl
    19 H OH propyl 3-(2-methophenyl)-benzyl
    20 H OH propyl 3-(2-naphthyl)benzyl
    21 H H propyl 3-(4-methoxyphenyl)-benzyl
    22 H H propyl 3-(3-fluorophenyl)-benzyl
    23 H H propyl 3-(4-F3C-phenyl)benzyl
    24 H H propyl 3-(2,4-Cl2-phenyl)benzyl
    25 H H propyl 3-(4-H3C-phenyl)benzyl
    26 H H propyl 3-(4-H3CO-phenyl)benzyl
    27 H H propyl 3-(3-Cl,4-F-phenyl)benzyl
    28 H H propyl 3-(3-H3CO-phenyl)benzyl
    29 H H propyl 3-(2-H3CO-phenyl)benzyl
    30 H H propyl 3-(4-H3CO-phenyl)-pyrid-5-
    ylmethyl
    31 H H propyl 3-(4-F3C-phenyl)-pyrid-5-
    ylmethyl
    32 H H propyl 3-(3-Cl,4-F-phenyl)-pyrid-
    5-ylmethyl
    33 H n-butyl propyl 3-phenoxybenzyl
    34 H 2-furyl- propyl 3-phenoxybenzyl
    methyl
    35 H C5H9 propyl 3-phenoxybenzyl
    36 H cinnamyl propyl 3-phenoxybenzyl
    37 H H allyl benzophenone-3-yl-methyl
    38 H H propyl benzophenone-3-yl-methyl
    39 H H propyl 4-(4-F3C-phenyl)benzyl
     40* H H i-butyl 3-(2-tetrazolyl-phenyl)-
    R5 = propyl benzyl
     41* H H i-butyl 3-phenoxybenzyl
    R5 = propyl
    43 H H H 3-phenoxybenzyl

    *For these compounds the i-butyl substituent on the carbon adjacent to CR3 in the captioned figure is actually n-propyl.
  • [1920]
    For these compounds the i-butyl substituent on the carbon adjacent to CR3 in the captioned figure is actually n-propyl.
  • [1921]
    Table 2 demonstrates representative compounds envisaged within the scope of the present invention. Each formulae at the start of Table 2 are intended to be paired with each entry in the table which follows.
  • [1922]
    For example the compound (2R,3S) N1-[(3S)-hexahydro-1-(3-(3,4-dimethoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide is represented by Example #139-A-j, which comprises the core A, succinate j, and entry #139.
  • [1923]
    For example the compound (2R,3S) N1-[6,7-dihydro-5-(3-(3,4-dimethoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide is represented by Example #139-B-j, which comprises the core B, succinate j, and entry #139.
  • [1924]
    For example the compound (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3,4-dimethoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide, is represented by Example #139-C-ab, which comprises the core C, succinate ab, and entry #139.
    TABLE 2
    A B
    C D
    E F
    G H
    J K
    wherein R3 and R5 are:
    a b c
    d e f
    g h i
    j k l
    m n o
    p q r
    s t u
    v w x
    v z aa
    ab ac ad
    ae af ag
    ah ai aj
    ak al am
    an ao ap
    aq ar as
    at au av
    aw ax ay
    az ba bb
    bc bd be
    bf bg bh
    bi bj bk
    bl bm bn
    bo bp bq
    br bs bt
    Ex # W X Y Z
    100 —CH2 phen-1,3-diyl bond phenyl
    101 —CH2 phen-1,3-diyl bond 3,3-diphenylmethyl
    102 —CH2 phen-1,3-diyl bond 2-F-phenyl
    103 —CH2 phen-1,3-diyl bond 3-F-phenyl
    104 —CH2 phen-1,3-diyl bond 4-F-phenyl
    105 —CH2 phen-1,3-diyl bond 2-Cl-phenyl
    106 —CH2 phen-1,3-diyl bond 3-Cl-phenyl
    107 —CH2 phen-1,3-diyl bond 4-Cl-phenyl
    108 —CH2 phen-1,3-diyl bond 2-Me-phenyl
    109 —CH2 phen-1,3-diyl bond 3-Me-phenyl
    110 —CH2 phen-1,3-diyl bond 4-Me-phenyl
    111 —CH2 phen-1,3-diyl bond 2-MeO-phenyl
    112 —CH2 phen-1,3-diyl bond 3-MeO-phenyl
    113 —CH2 phen-1,3-diyl bond 4-MeO-phenyl
    114 —CH2 phen-1,3-diyl bond 2-MeS-phenyl
    115 —CH2 phen-1,3-diyl bond 3-MeS-phenyl
    116 —CH2 phen-1,3-diyl bond 4-MeS-phenyl
    117 —CH2 phen-1,3-diyl bond 2-F3C-phenyl
    118 —CH2 phen-1,3-diyl bond 3-F3C-phenyl
    119 —CH2 phen-1,3-diyl bond 4-F3C-phenyl
    120 —CH2 phen-1,3-diyl bond 2,3-diF-phenyl
    121 —CH2 phen-1,3-diyl bond 2,4-diF-phenyl
    122 —CH2 phen-1,3-diyl bond 2,5-diF-phenyl
    123 —CH2 phen-1,3-diyl bond 2,6-diF-phenyl
    124 —CH2 phen-1,3-diyl bond 3,4-diF-phenyl
    125 —CH2 phen-1,3-diyl bond 3,5-diF-phenyl
    126 —CH2 phen-1,3-diyl bond 2,3-diCl-phenyl
    127 —CH2 phen-1,3-diyl bond 2,4-diCl-phenyl
    128 —CH2 phen-1,3-diyl bond 2,5-diCl-phenyl
    129 —CH2 phen-1,3-diyl bond 2,6-diCl-phenyl
    130 —CH2 phen-1,3-diyl bond 3,4-diCl-phenyl
    131 —CH2 phen-1,3-diyl bond 3,5-diCl-phenyl
    132 —CH2 phen-1,3-diyl bond 2-Cl-3-F-phenyl
    133 —CH2 phen-1,3-diyl bond 2-Cl-4-F-phenyl
    134 —CH2 phen-1,3-diyl bond 2-Cl-5-F-phenyl
    135 —CH2 phen-1,3-diyl bond 3-Cl-4-F-phenyl
    136 —CH2 phen-1,3-diyl bond 3-Cl-5-F-phenyl
    137 —CH2 phen-1,3-diyl bond 4-Cl-2-F-phenyl
    138 —CH2 phen-1,3-diyl bond 4-Cl-3-F-phenyl
    139 —CH2 phen-1,3-diyl bond 2,3-diMeO-phenyl
    140 —CH2 phen-1,3-diyl bond 2,4-diMeO-phenyl
    141 —CH2 phen-1,3-diyl bond 2,5-diMeO-phenyl
    142 —CH2 phen-1,3-diyl bond 2,6-diMeO-phenyl
    143 —CH2 phen-1,3-diyl bond 3,4-diMeO-phenyl
    144 —CH2 phen-1,3-diyl bond 3,5-diMeO-phenyl
    145 —CH2 phen-1,3-diyl bond cyclopropyl
    146 —CH2 phen-1,3-diyl bond cyclobutyl
    147 —CH2 phen-1,3-diyl bond cyclopentyl
    148 —CH2 phen-1,3-diyl bond cyclohexyl
    149 —CH2 phen-1,3-diyl bond 2-furanyl
    150 —CH2 phen-1,3-diyl bond 2-thienyl
    151 —CH2 phen-1,3-diyl bond 2-imidazolyl
    152 —CH2 phen-1,3-diyl bond 2-pyridyl
    153 —CH2 phen-1,3-diyl bond 3-pyridyl
    154 —CH2 phen-1,3-diyl bond 4-pyridyl
    155 —CH2 phen-1,3-diyl bond N-morpholinyl
    156 —CH2 phen-1,3-diyl bond N-piperidinyl
    157 —CH2 phen-1,3-diyl bond 3-Me-2-pyridyl
    158 —CH2 phen-1,3-diyl bond 4-Me-2-pyridyl
    159 —CH2 phen-1,3-diyl bond 1-indolyl
    160 —CH2 phen-1,3-diyl bond 2-benzothienyl
    161 —CH2 phen-1,3-diyl bond 2-benzofuranyl
    162 —CH2 phen-1,3-diyl bond 1-benzimidazole
    163 —CH2 phen-1,3-diyl bond 2-naphthyl
    164 —CH2 pyridin-3,5-diyl bond phenyl
    165 —CH2 pyridin-3,5-diyl bond 3,3-diphenylmethyl
    166 —CH2 pyridin-3,5-diyl bond 2-F-phenyl
    167 —CH2 pyridin-3,5-diyl bond 3-F-phenyl
    168 —CH2 pyridin-3,5-diyl bond 4-F-phenyl
    169 —CH2 pyridin-3,5-diyl bond 2-Cl-phenyl
    170 —CH2 pyridin-3,5-diyl bond 3-Cl-phenyl
    171 —CH2 pyridin-3,5-diyl bond 4-Cl-phenyl
    172 —CH2 pyridin-3,5-diyl bond 2-Me-phenyl
    173 —CH2 pyridin-3,5-diyl bond 3-Me-phenyl
    174 —CH2 pyridin-3,5-diyl bond 4-Me-phenyl
    175 —CH2 pyridin-3,5-diyl bond 2-MeO-phenyl
    176 —CH2 pyridin-3,5-diyl bond 3-MeO-phenyl
    177 —CH2 pyridin-3,5-diyl bond 4-MeO-phenyl
    178 —CH2 pyridin-3,5-diyl bond 2-MeS-phenyl
    179 —CH2 pyridin-3,5-diyl bond 3-MeS-phenyl
    180 —CH2 pyridin-3,5-diyl bond 4-MeS-phenyl
    181 —CH2 pyridin-3,5-diyl bond 2-F3C-phenyl
    182 —CH2 pyridin-3,5-diyl bond 3-F3C-phenyl
    183 —CH2 pyridin-3,5-diyl bond 4-F3C-phenyl
    184 —CH2 pyridin-3,5-diyl bond 2,3-diF-phenyl
    185 —CH2 pyridin-3,5-diyl bond 2,4-diF-phenyl
    186 —CH2 pyridin-3,5-diyl bond 2,5-diF-phenyl
    187 —CH2 pyridin-3,5-diyl bond 2,6-diF-phenyl
    188 —CH2 pyridin-3,5-diyl bond 3,4-diF-phenyl
    189 —CH2 pyridin-3,5-diyl bond 3,5-diF-phenyl
    190 —CH2 pyridin-3,5-diyl bond 2,3-diCl-phenyl
    191 —CH2 pyridin-3,5-diyl bond 2,4-diCl-phenyl
    192 —CH2 pyridin-3,5-diyl bond 2,5-diCl-phenyl
    193 —CH2 pyridin-3,5-diyl bond 2,6-diCl-phenyl
    194 —CH2 pyridin-3,5-diyl bond 3,4-diCl-phenyl
    195 —CH2 pyridin-3,5-diyl bond 3,5-diCl-phenyl
    196 —CH2 pyridin-3,5-diyl bond 2-Cl-3-F-phenyl
    197 —CH2 pyridin-3,5-diyl bond 2-Cl-4-F-phenyl
    198 —CH2 pyridin-3,5-diyl bond 2-Cl-5-F-phenyl
    199 —CH2 pyridin-3,5-diyl bond 3-Cl-4-F-phenyl
    200 —CH2 pyridin-3,5-diyl bond 3-Cl-5-F-phenyl
    201 —CH2 pyridin-3,5-diyl bond 4-Cl-2-F-phenyl
    202 —CH2 pyridin-3,5-diyl bond 4-Cl-3-F-phenyl
    203 —CH2 pyridin-3,5-diyl bond 2,3-diMeO-phenyl
    204 —CH2 pyridin-3,5-diyl bond 2,4-diMeO-phenyl
    205 —CH2 pyridin-3,5-diyl bond 2,5-diMeO-phenyl
    206 —CH2 pyridin-3,5-diyl bond 2,6-diMeO-phenyl
    207 —CH2 pyridin-3,5-diyl bond 3,4-diMeO-phenyl
    208 —CH2 pyridin-3,5-diyl bond 3,5-diMeO-phenyl
    209 —CH2 pyridin-3,5-diyl bond cyclopropyl
    210 —CH2 pyridin-3,5-diyl bond cyclobutyl
    211 —CH2 pyridin-3,5-diyl bond cyclopentyl
    212 —CH2 pyridin-3,5-diyl bond cyclohexyl
    213 —CH2 pyridin-3,5-diyl bond 2-furanyl
    214 —CH2 pyridin-3,5-diyl bond 2-thienyl
    215 —CH2 pyridin-3,5-diyl bond 2-imidazolyl
    216 —CH2 pyridin-3,5-diyl bond 2-pyridyl
    217 —CH2 pyridin-3,5-diyl bond 3-pyridyl
    218 —CH2 pyridin-3,5-diyl bond 4-pyridyl
    219 —CH2 pyridin-3,5-diyl bond N-morpholinyl
    220 —CH2 pyridin-3,5-diyl bond N-piperidinyl
    221 —CH2 pyridin-3,5-diyl bond 3-Me-2-pyridyl
    222 —CH2 pyridin-3,5-diyl bond 4-Me-2-pyridyl
    223 —CH2 pyridin-3,5-diyl bond 1-indolyl
    224 —CH2 pyridin-3,5-diyl bond 2-benzothienyl
    225 —CH2 pyridin-3,5-diyl bond 2-benzofuranyl
    226 —CH2 pyridin-3,5-diyl bond 1-benzimidazole
    227 —CH2 pyridin-3,5-diyl bond 2-naphthyl
    228 —CH2 pyridin-2,6-diyl bond phenyl
    229 —CH2 pyridin-2,6-diyl bond 3,3-diphenylmethyl
    230 —CH2 pyridin-2,6-diyl bond 2-F-phenyl
    231 —CH2 pyridin-2,6-diyl bond 3-F-phenyl
    232 —CH2 pyridin-2,6-diyl bond 4-F-phenyl
    233 —CH2 pyridin-2,6-diyl bond 2-Cl-phenyl
    234 —CH2 pyridin-2,6-diyl bond 3-Cl-phenyl
    235 —CH2 pyridin-2,6-diyl bond 4-Cl-phenyl
    236 —CH2 pyridin-2,6-diyl bond 2-Me-phenyl
    237 —CH2 pyridin-2,6-diyl bond 3-Me-phenyl
    238 —CH2 pyrldin-2,6-diyl bond 4-Me-phenyl
    239 —CH2 pyridin-2,6-diyl bond 2-MeO-phenyl
    240 —CH2 pyridin-2,6-diyl bond 3-MeO-phenyl
    241 —CH2 pyridin-2,6-diyl bond 4-MeO-phenyl
    242 —CH2 pyridin-2,6-diyl bond 2-MeS-phenyl
    243 —CH2 pyridin-2,6-diyl bond 3-MeS-phenyl
    244 —CH2 pyridin-2,6-diyl bond 4-MeS-phenyl
    245 —CH2 pyridin-2,6-diyl bond 2-F3C-phenyl
    246 —CH2 pyridin-2,6-diyl bond 3-F3C-phenyl
    247 —CH2 pyridin-2,6-diyl bond 4-F3C-phenyl
    248 —CH2 pyridin-2,6-diyl bond 2,3-diF-phenyl
    249 —CH2 pyridin-2,6-diyl bond 2,4-diF-phenyl
    250 —CH2 pyridin-2,6-diyl bond 2,5-diF-phenyl
    251 —CH2 pyridin-2,6-diyl bond 2,6-diF-phenyl
    252 —CH2 pyridin-2,6-diyl bond 3,4-diF-phenyl
    253 —CH2 pyridin-2,6-diyl bond 3,5-diF-phenyl
    254 —CH2 pyridin-2,6-diyl bond 2,3-diCl-phenyl
    255 —CH2 pyridin-2,6-diyl bond 2,4-diCl-phenyl
    256 —CH2 pyridin-2,6-diyl bond 2,5-diCl-phenyl
    257 —CH2 pyridin-2,6-diyl bond 2,6-diCl-phenyl
    258 —CH2 pyridin-2,6-diyl bond 3,4-diCl-phenyl
    259 —CH2 pyridin-2,6-diyl bond 3,5-diCl-phenyl
    260 —CH2 pyridin-2,6-diyl bond 2-Cl-3-F-phenyl
    261 —CH2 pyridin-2,6-diyl bond 2-Cl-4-F-phenyl
    262 —CH2 pyridin-2,6-diyl bond 2-Cl-5-F-phenyl
    263 —CH2 pyridin-2,6-diyl bond 3-Cl-4-F-phenyl
    264 —CH2 pyridin-2,6-diyl bond 3-Cl-5-F-phenyl
    265 —CH2 pyridin-2,6-diyl bond 4-Cl-2-F-phenyl
    266 —CH2 pyridin-2,6-diyl bond 4-Cl-3-F-phenyl
    267 —CH2 pyridin-2,6-diyl bond 2,3-diMeO-phenyl
    268 —CH2 pyridin-2,6-diyl bond 2,4-diMeO-phenyl
    269 —CH2 pyridin-2,6-diyl bond 2,5-diMeO-phenyl
    270 —CH2 pyridin-2,6-diyl bond 2,6-diMeO-phenyl
    271 —CH2 pyridin-2,6-diyl bond 3,4-diMeO-phenyl
    272 —CH2 pyridin-2,6-diyl bond 3,5-diMeO-phenyl
    273 —CH2 pyridin-2,6-diyl bond cyclopropyl
    274 —CH2 pyridin-2,6-diyl bond cyclobutyl
    275 —CH2 pyridin-2,6-diyl bond cyclopentyl
    276 —CH2 pyridin-2,6-diyl bond cyclohexyl
    277 —CH2 pyridin-2,6-diyl bond 2-furanyl
    278 —CH2 pyridin-2,6-diyl bond 2-thienyl
    279 —CH2 pyridin-2,6-diyl bond 2-imidazolyl
    280 —CH2 pyridin-2,6-diyl bond 2-pyridyl
    281 —CH2 pyridin-2,6-diyl bond 3-pyridyl
    282 —CH2 pyridin-2,6-diyl bond 4-pyridyl
    283 —CH2 pyridin-2,6-diyl bond N-morpholinyl
    284 —CH2 pyridin-2,6-diyl bond N-piperidinyl
    285 —CH2 pyridin-2,6-diyl bond 3-Me-2-pyridyl
    286 —CH2 pyridin-2,6-diyl bond 4-Me-2-pyridyl
    287 —CH2 pyridin-2,6-diyl bond 1-indolyl
    288 —CH2 pyridin-2,6-diyl bond 2-benzothienyl
    289 —CH2 pyridin-2,6-diyl bond 2-benzofuranyl
    290 —CH2 pyridin-2,6-diyl bond 1-benzimidazole
    291 —CH2 pyridin-2,6-diyl bond 2-naphthyl
    292 —CH2 pyridin-2,4-diyl bond phenyl
    293 —CH2 pyridin-2,4-diyl bond 3,3-diphenylmethyl
    294 —CH2 pyridin-2,4-diyl bond 2-F-phenyl
    295 —CH2 pyridin-2,4-diyl bond 3-F-phenyl
    296 —CH2 pyridin-2,4-diyl bond 4-F-phenyl
    297 —CH2 pyridin-2,4-diyl bond 2-Cl-phenyl
    298 —CH2 pyridin-2,4-diyl bond 3-Cl-phenyl
    299 —CH2 pyridin-2,4-diyl bond 4-Cl-phenyl
    300 —CH2 pyridin-2,4-diyl bond 2-Me-phenyl
    301 —CH2 pyridin-2,4-diyl bond 3-Me-phenyl
    302 —CH2 pyridin-2,4-diyl bond 4-Me-phenyl
    303 —CH2 pyridin-2,4-diyl bond 2-MeO-phenyl
    304 —CH2 pyridin-2,4-diyl bond 3-MeO-phenyl
    305 —CH2 pyridin-2,4-diyl bond 4-MeO-phenyl
    306 —CH2 pyridin-2,4-diyl bond 2-MeS-phenyl
    307 —CH2 pyridin-2,4-diyl bond 3-MeS-phenyl
    308 —CH2 pyridin-2,4-diyl bond 4-MeS-phenyl
    309 —CH2 pyridin-2,4-diyl bond 2-F3C-phenyl
    310 —CH2 pyridin-2,4-diyl bond 3-F3C-phenyl
    311 —CH2 pyridin-2,4-diyl bond 4-F3C-phenyl
    312 —CH2 pyridin-2,4-diyl bond 2,3-diF-phenyl
    313 —CH2 pyridin-2,4-diyl bond 2,4-diF-phenyl
    314 —CH2 pyridin-2,4-diyl bond 2,5-diF-phenyl
    315 —CH2 pyridin-2,4-diyl bond 2,6-diF-phenyl
    316 —CH2 pyridin-2,4-diyl bond 3,4-diF-phenyl
    317 —CH2 pyridin-2,4-diyl bond 3,5-diF-phenyl
    318 —CH2 pyridin-2,4-diyl bond 2,3-diCl-phenyl
    319 —CH2 pyridin-2,4-diyl bond 2,4-diCl-phenyl
    320 —CH2 pyridin-2,4-diyl bond 2,5-diCl-phenyl
    321 —CH2 pyridin-2,4-diyl bond 2,6-diCl-phenyl
    322 —CH2 pyridin-2,4-diyl bond 3,4-diCl-phenyl
    323 —CH2 pyridin-2,4-diyl bond 3,5-diCl-phenyl
    324 —CH2 pyridin-2,4-diyl bond 2-Cl-3-F-phenyl
    325 —CH2 pyridin-2,4-diyl bond 2-Cl-4-F-phenyl
    326 —CH2 pyridin-2,4-diyl bond 2-Cl-5-F-phenyl
    327 —CH2 pyridin-2,4-diyl bond 3-Cl-4-F-phenyl
    328 —CH2 pyridin-2,4-diyl bond 3-Cl-5-F-phenyl
    329 —CH2 pyridin-2,4-diyl bond 4-Cl-2-F-phenyl
    330 —CH2 pyridin-2,4-diyl bond 4-Cl-3-F-phenyl
    331 —CH2 pyridin-2,4-diyl bond 2,3-diMeO-phenyl
    332 —CH2 pyridin-2,4-diyl bond 2,4-diMeO-phenyl
    333 —CH2 pyridin-2,4-diyl bond 2,5-diMeO-phenyl
    334 —CH2 pyridin-2,4-diyl bond 2,6-diMeO-phenyl
    335 —CH2 pyridin-2,4-diyl bond 3,4-diMeO-phenyl
    336 —CH2 pyridin-2,4-diyl bond 3,5-diMeO-phenyl
    337 —CH2 pyridin-2,4-diyl bond cyclopropyl
    338 —CH2 pyridin-2,4-diyl bond cyclobutyl
    339 —CH2 pyridin-2,4-diyl bond cyclopentyl
    340 —CH2 pyridin-2,4-diyl bond cyclohexyl
    341 —CH2 pyridin-2,4-diyl bond 2-furanyl
    342 —CH2 pyridin-2,4-diyl bond 2-thienyl
    343 —CH2 pyridin-2,4-diyl bond 2-imidazolyl
    344 —CH2 pyridin-2,4-diyl bond 2-pyridyl
    345 —CH2 pyridin-2,4-diyl bond 3-pyridyl
    346 —CH2 pyridin-2,4-diyl bond 4-pyridyl
    347 —CH2 pyridin-2,4-diyl bond N-morpholinyl
    348 —CH2 pyridin-2,4-diyl bond N-piperidinyl
    349 —CH2 pyridin-2,4-diyl bond 3-Me-2-pyridyl
    350 —CH2 pyridin-2,4-diyl bond 4-Me-2-pyridyl
    351 —CH2 pyridin-2,4-diyl bond 1-indolyl
    352 —CH2 pyridin-2,4-diyl bond 2-benzothienyl
    353 —CH2 pyridin-2,4-diyl bond 2-benzofuranyl
    354 —CH2 pyridin-2,4-diyl bond 1-benzimidazole
    355 —CH2 pyridin-2,4-diyl bond 2-naphthyl
    356 —CH2 pyridin-4,2-diyl bond phenyl
    357 —CH2 pyridin-4,2-diyl bond 3,3-diphenylmethyl
    358 —CH2 pyridin-4,2-diyl bond 2-F-phenyl
    359 —CH2 pyridin-4,2-diyl bond 3-F-phenyl
    360 —CH2 pyridin-4,2-diyl bond 4-F-phenyl
    361 —CH2 pyridin-4,2-diyl bond 2-Cl-phenyl
    362 —CH2 pyridin-4,2-diyl bond 3-Cl-phenyl
    363 —CH2 pyridin-4,2-diyl bond 4-Cl-phenyl
    364 —CH2 pyridin-4,2-diyl bond 2-Me-phenyl
    365 —CH2 pyridin-4,2-diyl bond 3-Me-phenyl
    366 —CH2 pyridin-4,2-diyl bond 4-Me-phenyl
    367 —CH2 pyridin-4,2-diyl bond 2-MeO-phenyl
    368 —CH2 pyridin-4,2-diyl bond 3-MeO-phenyl
    369 —CH2 pyridin-4,2-diyl bond 4-MeO-phenyl
    370 —CH2 pyridin-4,2-diyl bond 2-MeS-phenyl
    371 —CH2 pyridin-4,2-diyl bond 3-MeS-phenyl
    372 —CH2 pyridin-4,2-diyl bond 4-MeS-phenyl
    373 —CH2 pyridin-4,2-diyl bond 2-F3C-phenyl
    374 —CH2 pyridin-4,2-diyl bond 3-F3C-phenyl
    375 —CH2 pyridin-4,2-diyl bond 4-F3C-phenyl
    376 —CH2 pyridin-4,2-diyl bond 2,3-diF-phenyl
    377 —CH2 pyridin-4,2-diyl bond 2,4-diF-phenyl
    378 —CH2 pyridin-4,2-diyl bond 2,5-diF-phenyl
    379 —CH2 pyridin-4,2-diyl bond 2,6-diF-phenyl
    380 —CH2 pyridin-4,2-diyl bond 3,4-diF-phenyl
    381 —CH2 pyridin-4,2-diyl bond 3,5-diF-phenyl
    382 —CH2 pyridin-4,2-diyl bond 2,3-diCl-phenyl
    383 —CH2 pyridin-4,2-diyl bond 2,4-diCl-phenyl
    384 —CH2 pyridin-4,2-diyl bond 2,5-diCl-phenyl
    385 —CH2 pyridin-4,2-diyl bond 2,6-diCl-phenyl
    386 —CH2 pyridin-4,2-diyl bond 3,4-diCl-phenyl
    387 —CH2 pyridin-4,2-diyl bond 3,5-diCl-phenyl
    388 —CH2 pyridin-4,2-diyl bond 2-Cl-3-F-phenyl
    389 —CH2 pyridin-4,2-diyl bond 2-Cl-4-F-phenyl
    390 —CH2 pyridin-4,2-diyl bond 2-Cl-5-F-phenyl
    391 —CH2 pyridin-4,2-diyl bond 3-Cl-4-F-phenyl
    392 —CH2 pyridin-4,2-diyl bond 3-Cl-5-F-phenyl
    393 —CH2 pyridin-4,2-diyl bond 4-Cl-2-F-phenyl
    394 —CH2 pyridin-4,2-diyl bond 4-Cl-3-F-phenyl
    395 —CH2 pyridin-4,2-diyl bond 2,3-diMeO-phenyl
    396 —CH2 pyridin-4,2-diyl bond 2,4-diMeO-phenyl
    397 —CH2 pyridin-4,2-diyl bond 2,5-diMeO-phenyl
    398 —CH2 pyridin-4,2-diyl bond 2,6-diMeO-phenyl
    399 —CH2 pyridin-4,2-diyl bond 3,4-diMeO-phenyl
    400 —CH2 pyridin-4,2-diyl bond 3,5-diMeO-phenyl
    401 —CH2 pyridin-4,2-diyl bond cyclopropyl
    402 —CH2 pyridin-4,2-diyl bond cyclobutyl
    403 —CH2 pyridin-4,2-diyl bond cyclopentyl
    404 —CH2 pyridin-4,2-diyl bond cyclohexyl
    405 —CH2 pyridin-4,2-diyl bond 2-furanyl
    406 —CH2 pyridin-4,2-diyl bond 2-thienyl
    407 —CH2 pyridin-4,2-diyl bond 2-imidazolyl
    408 —CH2 pyridin-4,2-diyl bond 2-pyridyl
    409 —CH2 pyridin-4,2-diyl bond 3-pyridyl
    410 —CH2 pyridin-4,2-diyl bond 4-pyridyl
    411 —CH2 pyridin-4,2-diyl bond N-morpholinyl
    412 —CH2 pyridin-4,2-diyl bond N-piperidinyl
    413 —CH2 pyridin-4,2-diyl bond 3-Me-2-pyridyl
    414 —CH2 pyridin-4,2-diyl bond 4-Me-2-pyridyl
    415 —CH2 pyridin-4,2-diyl bond 1-indolyl
    416 —CH2 pyridin-4,2-diyl bond 2-benzothienyl
    417 —CH2 pyridin-4,2-diyl bond 2-benzofuranyl
    418 —CH2 pyridin-4,2-diyl bond 1-benzimidazole
    419 —CH2 pyridin-4,2-diyl bond 2-naphthyl
    420 —CH2 piperidin-1,3-diyl bond phenyl
    421 —CH2 piperidin-1,3-diyl bond 3,3-diphenylmethyl
    422 —CH2 piperidin-1,3-diyl bond 2-F-phenyl
    423 —CH2 piperidin-1,3-diyl bond 3-F-phenyl
    424 —CH2 piperidin-1,3-diyl bond 4-F-phenyl
    425 —CH2 piperidin-1,3-diyl bond 2-Cl-phenyl
    426 —CH2 piperidin-1,3-diyl bond 3-Cl-phenyl
    427 —CH2 piperidin-1,3-diyl bond 4-Cl-phenyl
    428 —CH2 piperidin-1,3-diyl bond 2-Me-phenyl
    429 —CH2 piperidin-1,3-diyl bond 3-Me-phenyl
    430 —CH2 piperidin-1,3-diyl bond 4-Me-phenyl
    431 —CH2 piperidin-1,3-diyl bond 2-MeO-phenyl
    432 —CH2 piperidin-1,3-diyl bond 3-MeO-phenyl
    433 —CH2 piperidin-1,3-diyl bond 4-MeO-phenyl
    434 —CH2 piperidin-1,3-diyl bond 2-MeS-phenyl
    435 —CH2 piperidin-1,3-diyl bond 3-MeS-phenyl
    436 —CH2 piperidin-1,3-diyl bond 4-MeS-phenyl
    437 —CH2 piperidin-1,3-diyl bond 2-F3C-phenyl
    438 —CH2 piperidin-1,3-diyl bond 3-F3C-phenyl
    439 —CH2 piperidin-1,3-diyl bond 4-F3C-phenyl
    440 —CH2 piperidin-1,3-diyl bond 2,3-diF-phenyl
    441 —CH2 piperidin-1,3-diyl bond 2,4-diF-phenyl
    442 —CH2 piperidin-1,3-diyl bond 2,5-diF-phenyl
    443 —CH2 piperidin-1,3-diyl bond 2,6-diF-phenyl
    444 —CH2 piperidin-1,3-diyl bond 3,4-diF-phenyl
    445 —CH2 piperidin-1,3-diyl bond 3,5-diF-phenyl
    446 —CH2 piperidin-1,3-diyl bond 2,3-diCl-phenyl
    447 —CH2 piperidin-1,3-diyl bond 2,4-diCl-phenyl
    448 —CH2 piperidin-1,3-diyl bond 2,5-diCl-phenyl
    449 —CH2 piperidin-1,3-diyl bond 2,6-diCl-phenyl
    450 —CH2 piperidin-1,3-diyl bond 3,4-diCl-phenyl
    451 —CH2 piperidin-1,3-diyl bond 3,5-diCl-phenyl
    452 —CH2 piperidin-1,3-diyl bond 2-Cl-3-F-phenyl
    453 —CH2 piperidin-1,3-diyl bond 2-Cl-4-F-phenyl
    454 —CH2 piperidin-1,3-diyl bond 2-Cl-5-F-phenyl
    455 —CH2 piperidin-1,3-diyl bond 3-Cl-4-F-phenyl
    456 —CH2 piperidin-1,3-diyl bond 3-Cl-5-F-phenyl
    457 —CH2 piperidin-1,3-diyl bond 4-Cl-2-F-phenyl
    458 —CH2 piperidin-1,3-diyl bond 4-Cl-3-F-phenyl
    459 —CH2 piperidin-1,3-diyl bond 2,3-diMeO-phenyl
    460 —CH2 piperidin-1,3-diyl bond 2,4-diMeO-phenyl
    461 —CH2 piperidin-1,3-diyl bond 2,5-diMeO-phenyl
    462 —CH2 piperidin-1,3-diyl bond 2,6-diMeO-phenyl
    463 —CH2 piperidin-1,3-diyl bond 3,4-diMeO-phenyl
    464 —CH2 piperidin-1,3-diyl bond 3,5-diMeO-phenyl
    465 —CH2 piperidin-1,3-diyl bond cyclopropyl
    466 —CH2 piperidin-1,3-diyl bond cyclobutyl
    467 —CH2 piperidin-1,3-diyl bond cyclopentyl
    468 —CH2 piperidin-1,3-diyl bond cyclohexyl
    469 —CH2 piperidin-1,3-diyl bond 2-furanyl
    470 —CH2 piperidin-1,3-diyl bond 2-thienyl
    471 —CH2 piperidin-1,3-diyl bond 2-imidazolyl
    472 —CH2 piperidin-1,3-diyl bond 2-pyridyl
    473 —CH2 piperidin-1,3-diyl bond 3-pyridyl
    474 —CH2 piperidin-1.3-diyl bond 4-pyridyl
    475 —CH2 piperidin-1,3-diyl bond N-morpholinyl
    476 —CH2 piperidin-1,3-diyl bond N-piperidinyl
    477 —CH2 piperidin-1,3-diyl bond 3-Me-2-pyridyl
    478 —CH2 piperidin-1,3-diyl bond 4-Me-2-pyridyl
    479 —CH2 piperidin-1,3-diyl bond 1-indolyl
    480 —CH2 piperidin-1,3-diyl bond 2-benzothienyl
    481 —CH2 piperidin-1,3-diyl bond 2-benzofuranyl
    482 —CH2 piperidin-1,3-diyl bond 1-benzimidazole
    483 —CH2 piperidin-1,3-diyl bond 2-naphthyl
    484 —CH2 piperidin-3,1-diyl bond phenyl
    485 —CH2 piperidin-3,1-diyl bond 3,3-diphenylmethyl
    486 —CH2 piperidin-3,1-diyl bond 2-F-phenyl
    487 —CH2 piperidin-3,1-diyl bond 3-F-phenyl
    488 —CH2 piperidin-3,1-diyl bond 4-F-phenyl
    489 —CH2 piperidin-3,1-diyl bond 2-Cl-phenyl
    490 —CH2 piperidin-3,1-diyl bond 3-Cl-phenyl
    491 —CH2 piperidin-3,1-diyl bond 4-Cl-phenyl
    492 —CH2 piperidin-3,1-diyl bond 2-Me-phenyl
    493 —CH2 piperidin-3,1-diyl bond 3-Me-phenyl
    494 —CH2 piperidin-3,1-diyl bond 4-Me-phenyl
    495 —CH2 piperidin-3,1-diyl bond 2-MeO-phenyl
    496 —CH2 piperidin-3,1-diyl bond 3-MeO-phenyl
    497 —CH2 piperidin-3,1-diyl bond 4-MeO-phenyl
    498 —CH2 piperidin-3,1-diyl bond 2-MeS-phenyl
    499 —CH2 piperidin-3,1-diyl bond 3-MeS-phenyl
    500 —CH2 piperidin-3,1-diyl bond 4-MeS-phenyl
    501 —CH2 piperidin-3,1-diyl bond 2-F3C-phenyl
    502 —CH2 piperidin-3,1-diyl bond 3-F3C-phenyl
    503 —CH2 piperidin-3,1-diyl bond 4-F3C-phenyl
    504 —CH2 piperidin-3,1-diyl bond 2,3-diF-phenyl
    505 —CH2 piperidin-3,1-diyl bond 2,4-diF-phenyl
    506 —CH2 piperidin-3,1-diyl bond 2,5-diF-phenyl
    507 —CH2 piperidin-3,1-diyl bond 2,6-diF-phenyl
    508 —CH2 piperidin-3,1-diyl bond 3,4-diF-phenyl
    509 —CH2 piperidin-3,1-diyl bond 3,5-diF-phenyl
    510 —CH2 piperidin-3,1-diyl bond 2,3-diCl-phenyl
    511 —CH2 piperidin-3,1-diyl bond 2,4-diCl-phenyl
    512 —CH2 piperidin-3,1-diyl bond 2,5-diCl-phenyl
    513 —CH2 piperidin-3,1-diyl bond 2,6-diCl-phenyl
    514 —CH2 piperidin-3,1-diyl bond 3,4-diCl-phenyl
    515 —CH2 piperidin-3,1-diyl bond 3,5-diCl-phenyl
    516 —CH2 piperidin-3,1-diyl bond 2-Cl-3-F-phenyl
    517 —CH2 piperidin-3,1-diyl bond 2-Cl-4-F-phenyl
    518 —CH2 piperidin-3,1-diyl bond 2-Cl-5-F-phenyl
    519 —CH2 piperidin-3,1-diyl bond 3-Cl-4-F-phenyl
    520 —CH2 piperidin-3,1-diyl bond 3-Cl-5-F-phenyl
    521 —CH2 piperidin-3,1-diyl bond 4-Cl-2-F-phenyl
    522 —CH2 piperidin-3,1-diyl bond 4-Cl-3-F-phenyl
    523 —CH2 piperidin-3,1-diyl bond 2,3-diMeO-phenyl
    524 —CH2 piperidin-3,1-diyl bond 2,4-diMeO-phenyl
    525 —CH2 piperidin-3,1-diyl bond 2,5-diMeO-phenyl
    526 —CH2 piperidin-3,1-diyl bond 2,6-diMeO-phenyl
    527 —CH2 piperidin-3,1-diyl bond 3,4-diMeO-phenyl
    528 —CH2 piperidin-3,1-diyl bond 3,5-diMeO-phenyl
    529 —CH2 piperidin-3,1-diyl bond cyclopropyl
    530 —CH2 piperidin-3,1-diyl bond cyclobutyl
    531 —CH2 piperidin-3,1-diyl bond cyclopentyl
    532 —CH2 piperidin-3,1-diyl bond cyclohexyl
    533 —CH2 piperidin-3,1-diyl bond 2-furanyl
    534 —CH2 piperidin-3,1-diyl bond 2-thienyl
    535 —CH2 piperidin-3,1-diyl bond 2-imidazolyl
    536 —CH2 piperidin-3,1-diyl bond 2-pyridyl
    537 —CH2 piperidin-3,1-diyl bond 3-pyridyl
    538 —CH2 piperidin-3,1-diyl bond 4-pyridyl
    539 —CH2 piperidin-3,1-diyl bond N-morpholinyl
    540 —CH2 piperidin-3,1-diyl bond N-piperidinyl
    541 —CH2 piperidin-3,1-diyl bond 3-Me-2-pyridyl
    542 —CH2 piperidin-3,1-diyl bond 4-Me-2-pyridyl
    543 —CH2 piperidin-3,1-diyl bond 1-indolyl
    544 —CH2 piperidin-3,1-diyl bond 2-benzothienyl
    545 —CH2 piperidin-3,1-diyl bond 2-benzofuranyl
    546 —CH2 piperidin-3,1-diyl bond 1-benzimidazole
    547 —CH2 piperidin-3,1-diyl bond 2-naphthyl
    548 —CH2 cyclohex-1,3-diyl bond phenyl
    549 —CH2 cyclohex-1,3-diyl bond 3,3-diphenylmethyl
    550 —CH2 cyclohex-1,3-diyl bond 2-F-phenyl
    551 —CH2 cyclohex-1,3-diyl bond 3-F-phenyl
    552 —CH2 cyclohex-1,3-diyl bond 4-F-phenyl
    553 —CH2 cyclohex-1,3-diyl bond 2-Cl-phenyl
    554 —CH2 cyclohex-1,3-diyl bond 3-Cl-phenyl
    555 —CH2 cyclohex-1,3-diyl bond 4-Cl-phenyl
    556 —CH2 cyclohex-1,3-diyl bond 2-Me-phenyl
    557 —CH2 cyclohex-1,3-diyl bond 3-Me-phenyl
    558 —CH2 cyclohex-1,3-diyl bond 4-Me-phenyl
    559 —CH2 cyclohex-1,3-diyl bond 2-MeO-phenyl
    560 —CH2 cyclohex-1,3-diyl bond 3-MeO-phenyl
    561 —CH2 cyclohex-1,3-diyl bond 4-MeO-phenyl
    562 —CH2 cyclohex-1,3-diyl bond 2-MeS-phenyl
    563 —CH2 cyclohex-1,3-diyl bond 3-MeS-phenyl
    564 —CH2 cyclohex-1,3-diyl bond 4-MeS-phenyl
    565 —CH2 cyclohex-1,3-diyl bond 2-F3C-phenyl
    566 —CH2 cyclohex-1,3-diyl bond 3-F3C-phenyl
    567 —CH2 cyclohex-1,3-diyl bond 4-F3C-phenyl
    568 —CH2 cyclohex-1,3-diyl bond 2,3-diF-phenyl
    569 —CH2 cyclohex-1,3-diyl bond 2,4-diF-phenyl
    570 —CH2 cyclohex-1,3-diyl bond 2,5-diF-phenyl
    571 —CH2 cyclohex-1,3-diyl bond 2,6-diF-phenyl
    572 —CH2 cyclohex-1,3-diyl bond 3,4-diF-phenyl
    573 —CH2 cyclohex-1,3-diyl bond 3,5-diF-phenyl
    574 —CH2 cyclohex-1,3-diyl bond 2,3-diCl-phenyl
    575 —CH2 cyclohex-1,3-diyl bond 2,4-diCl-phenyl
    576 —CH2 cyclohex-1,3-diyl bond 2,5-diCl-phenyl
    577 —CH2 cyclohex-1,3-diyl bond 2,6-diCl-phenyl
    578 —CH2 cyclohex-1,3-diyl bond 3,4-diCl-phenyl
    579 —CH2 cyclohex-1,3-diyl bond 3,5-diCl-phenyl
    580 —CH2 cyclohex-1,3-diyl bond 2-Cl-3-F-phenyl
    581 —CH2 cyclohex-1,3-diyl bond 2-Cl-4-F-phenyl
    582 —CH2 cyclohex-1,3-diyl bond 2-Cl-5-F-phenyl
    583 —CH2 cyclohex-1,3-diyl bond 3-Cl-4-F-phenyl
    584 —CH2 cyclohex-1,3-diyl bond 3-Cl-5-F-phenyl
    585 —CH2 cyclohex-1,3-diyl bond 4-Cl-2-F-phenyl
    586 —CH2 cyclohex-1,3-diyl bond 4-Cl-3-F-phenyl
    587 —CH2 cyclohex-1,3-diyl bond 2,3-diMeO-phenyl
    588 —CH2 cyclohex-1,3-diyl bond 2,4-diMeO-phenyl
    589 —CH2 cyclohex-1,3-diyl bond 2,5-diMeO-phenyl
    590 —CH2 cyclohex-1,3-diyl bond 2,6-diMeO-phenyl
    591 —CH2 cyclohex-1,3-diyl bond 3,4-diMeO-phenyl
    592 —CH2 cyclohex-1,3-diyl bond 3,5-diMeO-phenyl
    593 —CH2 cyclohex-1,3-diyl bond cyclopropyl
    594 —CH2 cyclohex-1,3-diyl bond cyclobutyl
    595 —CH2 cyclohex-1,3-diyl bond cyclopentyl
    596 —CH2 cyclohex-1,3-diyl bond cyclohexyl
    597 —CH2 cyclohex-1,3-diyl bond 2-furanyl
    598 —CH2 cyclohex-1,3-diyl bond 2-thienyl
    599 —CH2 cyclohex-1,3-diyl bond 2-imidazolyl
    600 —CH2 cyclohex-1,3-diyl bond 2-pyridyl
    601 —CH2 cyclohex-1,3-diyl bond 3-pyridyl
    602 —CH2 cyclohex-1,3-diyl bond 4-pyridyl
    603 —CH2 cyclohex-1,3-diyl bond N-morpholinyl
    604 —CH2 cyclohex-1,3-diyl bond N-piperidinyl
    605 —CH2 cyclohex-1,3-diyl bond 3-Me-2-pyridyl
    606 —CH2 cyclohex-1,3-diyl bond 4-Me-2-pyridyl
    607 —CH2 cyclohex-1,3-diyl bond 1-indolyl
    608 —CH2 cyclohex-1,3-diyl bond 2-benzothienyl
    609 —CH2 cyclohex-1,3-diyl bond 2-benzofuranyl
    610 —CH2 cyclohex-1,3-diyl bond 1-benzimidazole
    611 —CH2 cyclohex-1,3-diyl bond 2-naphthyl
    612 —CH2 cyclopropan-1,2-diyl bond phenyl
    613 —CH2 cyclopropan-1,2-diyl bond 3,3-diphenylmethyl
    614 —CH2 cyclopropan-1,2-diyl bond 2-F-phenyl
    615 —CH2 cyclopropan-1,2-diyl bond 3-F-phenyl
    616 —CH2 cyclopropan-1,2-diyl bond 4-F-phenyl
    617 —CH2 cyclopropan-1,2-diyl bond 2-Cl-phenyl
    618 —CH2 cyclopropan-1,2-diyl bond 3-Cl-phenyl
    619 —CH2 cyclopropan-1,2-diyl bond 4-Cl-phenyl
    620 —CH2 cyclopropan-1,2-diyl bond 2-Me-phenyl
    621 —CH2 cyclopropan-1,2-diyl bond 3-Me-phenyl
    622 —CH2 cyclopropan-1,2-diyl bond 4-Me-phenyl
    623 —CH2 cyclopropan-1,2-diyl bond 2-MeO-phenyl
    624 —CH2 cyclopropan-1,2-diyl bond 3-MeO-phenyl
    625 —CH2 cyclopropan-1,2-diyl bond 4-MeO-phenyl
    626 —CH2 cyclopropan-1,2-diyl bond 2-MeS-phenyl
    627 —CH2 cyclopropan-1,2-diyl bond 3-MeS-phenyl
    628 —CH2 cyclopropan-1,2-diyl bond 4-MeS-phenyl
    629 —CH2 cyclopropan-1,2-diyl bond 2-F3C-phenyl
    630 —CH2 cyclopropan-1,2-diyl bond 3-F3C-phenyl
    631 —CH2 cyclopropan-1,2-diyl bond 4-F3C-phenyl
    632 —CH2 cyclopropan-1,2-diyl bond 2,3-diF-phenyl
    633 —CH2 cyclopropan-1,2-diyl bond 2,4-diF-phenyl
    634 —CH2 cyclopropan-1,2-diyl bond 2,5-diF-phenyl
    635 —CH2 cyclopropan-1,2-diyl bond 2,6-diF-phenyl
    636 —CH2 cyclopropan-1,2-diyl bond 3,4-diF-phenyl
    637 —CH2 cyclopropan-1,2-diyl bond 3,5-diF-phenyl
    638 —CH2 cyclopropan-1,2-diyl bond 2,3-diCl-phenyl
    639 —CH2 cyclopropan-1,2-diyl bond 2,4-diCl-phenyl
    640 —CH2 cyclopropan-1,2-diyl bond 2,5-diCl-phenyl
    641 —CH2 cyclopropan-1,2-diyl bond 2,6-diCl-phenyl
    642 —CH2 cyclopropan-1,2-diyl bond 3,4-diCl-phenyl
    643 —CH2 cyclopropan-1,2-diyl bond 3,5-diCl-phenyl
    644 —CH2 cyclopropan-1,2-diyl bond 2-Cl-3-F-phenyl
    645 —CH2 cyclopropan-1,2-diyl bond 2-Cl-4-F-phenyl
    646 —CH2 cyclopropan-1,2-diyl bond 2-Cl-5-F-phenyl
    647 —CH2 cyclopropan-1,2-diyl bond 3-Cl-4-F-phenyl
    648 —CH2 cyclopropan-1,2-diyl bond 3-Cl-5-F-phenyl
    649 —CH2 cyclopropan-1,2-diyl bond 4-Cl-2-F-phenyl
    650 —CH2 cyclopropan-1,2-diyl bond 4-Cl-3-F-phenyl
    651 —CH2 cyclopropan-1,2-diyl bond 2,3-diMeO-phenyl
    652 —CH2 cyclopropan-1,2-diyl bond 2,4-diMeO-phenyl
    653 —CH2 cyclopropan-1,2-diyl bond 2,5-diMeO-phenyl
    654 —CH2 cyclopropan-1,2-diyl bond 2,6-diMeO-phenyl
    655 —CH2 cyclopropan-1,2-diyl bond 3,4-diMeO-phenyl
    656 —CH2 cyclopropan-1,2-diyl bond 3,5-diMeO-phenyl
    657 —CH2 cyclopropan-1,2-diyl bond cyclopropyl
    658 —CH2 cyclopropan-1,2-diyl bond cyclobutyl
    659 —CH2 cyclopropan-1,2-diyl bond cyclopentyl
    660 —CH2 cyclopropan-1,2-diyl bond cyclohexyl
    661 —CH2 cyclopropan-1,2-diyl bond 2-furanyl
    662 —CH2 cyclopropan-1,2-diyl bond 2-thienyl
    663 —CH2 cyclopropan-1,2-diyl bond 2-imidazolyl
    664 —CH2 cyclopropan-1,2-diyl bond 2-pyridyl
    665 —CH2 cyclopropan-1,2-diyl bond 3-pyridyl
    666 —CH2 cyclopropan-1,2-diyl bond 4-pyridyl
    667 —CH2 cyclopropan-1,2-diyl bond N-morpholinyl
    668 —CH2 cyclopropan-1,2-diyl bond N-piperidinyl
    669 —CH2 cyclopropan-1,2-diyl bond 3-Me-2-pyridyl
    670 —CH2 cyclopropan-1,2-diyl bond 4-Me-2-pyridyl
    671 —CH2 cyclopropan-1,2-diyl bond 1-indolyl
    672 —CH2 cyclopropan-1,2-diyl bond 2-benzothienyl
    673 —CH2 cyclopropan-1,2-diyl bond 2-benzofuranyl
    674 —CH2 cyclopropan-1,2-diyl bond 1-benzimidazole
    675 —CH2 cyclopropan-1,2-diyl bond 2-naphthyl
    676 —CH2 cyclopentan-1,3-diyl bond phenyl
    677 —CH2 cyclopentan-1,3-diyl bond 3,3-diphenylmethyl
    678 —CH2 cyclopentan-1,3-diyl bond 2-F-phenyl
    679 —CH2 cyclopentan-1,3-diyl bond 3-F-phenyl
    680 —CH2 cyclopentan-1,3-diyl bond 4-F-phenyl
    681 —CH2 cyclopentan-1,3-diyl bond 2-Cl-phenyl
    682 —CH2 cyclopentan-1,3-diyl bond 3-Cl-phenyl
    683 —CH2 cyclopentan-1,3-diyl bond 4-Cl-phenyl
    684 —CH2 cyclopentan-1,3-diyl bond 2-Me-phenyl
    685 —CH2 cyclopentan-1,3-diyl bond 3-Me-phenyl
    686 —CH2 cyclopentan-1,3-diyl bond 4-Me-phenyl
    687 —CH2 cyclopentan-1,3-diyl bond 2-MeO-phenyl
    688 —CH2 cyclopentan-1,3-diyl bond 3-MeO-phenyl
    689 —CH2 cyclopentan-1,3-diyl bond 4-MeO-phenyl
    690 —CH2 cyclopentan-1,3-diyl bond 2-MeS-phenyl
    691 —CH2 cyclopentan-1,3-diyl bond 3-MeS-phenyl
    692 —CH2 cyclopentan-1,3-diyl bond 4-MeS-phenyl
    693 —CH2 cyclopentan-1,3-diyl bond 2-F3C-phenyl
    694 —CH2 cyclopentan-1,3-diyl bond 3-F3C-phenyl
    695 —CH2 cyclopentan-1,3-diyl bond 4-F3C-phenyl
    696 —CH2 cyclopentan-1,3-diyl bond 2,3-diF-phenyl
    697 —CH2 cyclopentan-1,3-diyl bond 2,4-diF-phenyl
    698 —CH2 cyclopentan-1,3-diyl bond 2,5-diF-phenyl
    699 —CH2 cyclopentan-1,3-diyl bond 2,6-diF-phenyl
    700 —CH2 cyclopentan-1,3-diyl bond 3,4-diF-phenyl
    701 —CH2 cyclopentan-1,3-diyl bond 3,5-diF-phenyl
    702 —CH2 cyclopentan-1,3-diyl bond 2,3-diCl-phenyl
    703 —CH2 cyclopentan-1,3-diyl bond 2,4-diCl-phenyl
    704 —CH2 cyclopentan-1,3-diyl bond 2,5-diCl-phenyl
    705 —CH2 cyclopentan-1,3-diyl bond 2,6-diCl-phenyl
    706 —CH2 cyclopentan-1,3-diyl bond 3,4-diCl-phenyl
    707 —CH2 cyclopentan-1,3-diyl bond 3,5-diCl-phenyl
    708 —CH2 cyclopentan-1,3-diyl bond 2-Cl-3-F-phenyl
    709 —CH2 cyclopentan-1,3-diyl bond 2-Cl-4-F-phenyl
    710 —CH2 cyclopentan-1,3-diyl bond 2-Cl-5-F-phenyl
    711 —CH2 cyclopentan-1,3-diyl bond 3-Cl-4-F-phenyl
    712 —CH2 cyclopentan-1,3-diyl bond 3-Cl-5-F-phenyl
    713 —CH2 cyclopentan-1,3-diyl bond 4-Cl-2-F-phenyl
    714 —CH2 cyclopentan-1,3-diyl bond 4-Cl-3-F-phenyl
    715 —CH2 cyclopentan-1,3-diyl bond 2,3-diMeO-phenyl
    716 —CH2 cyclopentan-1,3-diyl bond 2,4-diMeO-phenyl
    717 —CH2 cyclopentan-1,3-diyl bond 2,5-diMeO-phenyl
    718 —CH2 cyclopentan-1,3-diyl bond 2,6-diMeO-phenyl
    719 —CH2 cyclopentan-1,3-diyl bond 3,4-diMeO-phenyl
    720 —CH2 cyclopentan-1,3-diyl bond 3,5-diMeO-phenyl
    721 —CH2 cyclopentan-1,3-diyl bond cyclopropyl
    722 —CH2 cyclopentan-1,3-diyl bond cyclobutyl
    723 —CH2 cyclopentan-1,3-diyl bond cyclopentyl
    724 —CH2 cyclopentan-1,3-diyl bond cyclohexyl
    725 —CH2 cyclopentan-1,3-diyl bond 2-furanyl
    726 —CH2 cyclopentan-1,3-diyl bond 2-thienyl
    727 —CH2 cyclopentan-1,3-diyl bond 2-imidazolyl
    728 —CH2 cyclopentan-1,3-diyl bond 2-pyridyl
    729 —CH2 cyclopentan-1,3-diyl bond 3-pyridyl
    730 —CH2 cyclopentan-1,3-diyl bond 4-pyridyl
    731 —CH2 cyclopentan-1,3-diyl bond N-morpholinyl
    732 —CH2 cyclopentan-1,3-diyl bond N-piperidinyl
    733 —CH2 cyclopentan-1,3-diyl bond 3-Me-2-pyridyl
    734 —CH2 cyclopentan-1,3-diyl bond 4-Me-2-pyridyl
    735 —CH2 cyclopentan-1,3-diyl bond 1-indolyl
    736 —CH2 cyclopentan-1,3-diyl bond 2-benzothienyl
    737 —CH2 cyclopentan-1,3-diyl bond 2-benzofuranyl
    738 —CH2 cyclopentan-1,3-diyl bond 1-benzimidazole
    739 —CH2 cyclopentan-1,3-diyl bond 2-naphthyl
    740 —CH2 phen-1,3-diyl —O— phenyl
    741 —CH2 phen-1,3-diyl —O— 3,3-diphenylmethyl
    742 —CH2 phen-1,3-diyl —O— 2-F-phenyl
    743 —CH2 phen-1,3-diyl —O— 3-F-phenyl
    744 —CH2 phen-1,3-diyl —O— 4-F-phenyl
    745 —CH2 phen-1,3-diyl —O— 2-Cl-phenyl
    746 —CH2 phen-1,3-diyl —O— 3-Cl-phenyl
    747 —CH2 phen-1,3-diyl —O— 4-Cl-phenyl
    748 —CH2 phen-1,3-diyl —O— 2-Me-phenyl
    749 —CH2 phen-1,3-diyl —O— 3-Me-phenyl
    750 —CH2 phen-1,3-diyl —O— 4-Me-phenyl
    751 —CH2 phen-1,3-diyl —O— 2-MeO-phenyl
    752 —CH2 phen-1,3-diyl —O— 3-MeO-phenyl
    753 —CH2 phen-1,3-diyl —O— 4-MeO-phenyl
    754 —CH2 phen-1,3-diyl —O— 2-MeS-phenyl
    755 —CH2 phen-1,3-diyl —O— 3-MeS-phenyl
    756 —CH2 phen-1,3-diyl —O— 4-MeS-phenyl
    757 —CH2 phen-1,3-diyl —O— 2-F3C-phenyl
    758 —CH2 phen-1,3-diyl —O— 3-F3C-phenyl
    759 —CH2 phen-1,3-diyl —O— 4-F3C-phenyl
    760 —CH2 phen-1,3-diyl —O— 2,3-diF-phenyl
    761 —CH2 phen-1,3-diyl —O— 2,4-diF-phenyl
    762 —CH2 phen-1,3-diyl —O— 2,5-diF-phenyl
    763 —CH2 phen-1,3-diyl —O— 2,6-diF-phenyl
    764 —CH2 phen-1,3-diyl —O— 3,4-diF-phenyl
    765 —CH2 phen-1,3-diyl —O— 3,5-diF-phenyl
    766 —CH2 phen-1,3-diyl —O— 2,3-diCl-phenyl
    767 —CH2 phen-1,3-diyl —O— 2,4-diCl-phenyl
    768 —CH2 phen-1,3-diyl —O— 2,5-diCl-phenyl
    769 —CH2 phen-1,3-diyl —O— 2,6-diCl-phenyl
    770 —CH2 phen-1,3-diyl —O— 3,4-diCl-phenyl
    771 —CH2 phen-1,3-diyl —O— 3,5-diCl-phenyl
    772 —CH2 phen-1,3-diyl —O— 2-Cl-3-F-phenyl
    773 —CH2 phen-1,3-diyl —O— 2-Cl-4-F-phenyl
    774 —CH2 phen-1,3-diyl —O— 2-Cl-5-F-phenyl
    775 —CH2 phen-1,3-diyl —O— 3-Cl-4-F-phenyl
    776 —CH2 phen-1,3-diyl —O— 3-Cl-5-F-phenyl
    777 —CH2 phen-1,3-diyl —O— 4-Cl-2-F-phenyl
    778 —CH2 phen-1,3-diyl —O— 4-Cl-3-F-phenyl
    779 —CH2 phen-1,3-diyl —O— 2,3-diMeO-phenyl
    780 —CH2 phen-1,3-diyl —O— 2,4-diMeO-phenyl
    781 —CH2 phen-1,3-diyl —O— 2,5-diMeO-phenyl
    782 —CH2 phen-1,3-diyl —O— 2,6-diMeO-phenyl
    783 —CH2 phen-1,3-diyl —O— 3,4-diMeO-phenyl
    784 —CH2 phen-1,3-diyl —O— 3,5-diMeO-phenyl
    785 —CH2 phen-1,3-diyl —O— cyclopropyl
    786 —CH2 phen-1,3-diyl —O— cyclobutyl
    787 —CH2 phen-1,3-diyl —O— cyclopentyl
    788 —CH2 phen-1,3-diyl —O— cyclohexyl
    789 —CH2 phen-1,3-diyl —O— 2-furanyl
    790 —CH2 phen-1,3-diyl —O— 2-thienyl
    791 —CH2 phen-1,3-diyl CH2CH2 2-imidazolyl
    792 —CH2 phen-1,3-diyl —O— 2-pyridyl
    793 —CH2 phen-1,3-diyl —O— 3-pyridyl
    794 —CH2 phen-1,3-diyl —O— 4-pyridyl
    795 —CH2 phen-1,3-diyl CH2CH2 N-morpholinyl
    796 —CH2 phen-1,3-diyl CH2CH2 N-piperidinyl
    797 —CH2 phen-1,3-diyl —O— 3-Me-2-pyridyl
    798 —CH2 phen-1,3-diyl —O— 4-Me-2-pyridyl
    799 —CH2 phen-1,3-diyl CH2CH2 1-indolyl
    800 —CH2 phen-1,3-diyl —O— 2-benzothienyl
    801 —CH2 phen-1,3-diyl —O— 2-benzofuranyl
    802 —CH2 phen-1,3-diyl CH2CH2 1-benzimidazole
    803 —CH2 phen-1,3-diyl —O— 2-naphthyl
    804 —CH2 pyridin-3,5-diyl —O— phenyl
    805 —CH2 pyridin-3,5-diyl —O— 3,3-diphenylmethyl
    806 —CH2 pyridin-3,5-diyl —O— 2-F-phenyl
    807 —CH2 pyridin-3,5-diyl —O— 3-F-phenyl
    808 —CH2 pyridin-3,5-diyl —O— 4-F-phenyl
    809 —CH2 pyridin-3,5-diyl —O— 2-Cl-phenyl
    810 —CH2 pyridin-3,5-diyl —O— 3-Cl-phenyl
    811 —CH2 pyridin-3,5-diyl —O— 4-Cl-phenyl
    812 —CH2 pyridin-3,5-diyl —O— 2-Me-phenyl
    813 —CH2 pyridin-3,5-diyl —O— 3-Me-phenyl
    814 —CH2 pyridin-3,5-diyl —O— 4-Me-phenyl
    815 —CH2 pyridin-3,5-diyl —O— 2-MeO-phenyl
    816 —CH2 pyridin-3,5-diyl —O— 3-MeO-phenyl
    817 —CH2 pyridin-3,5-diyl —O— 4-MeO-phenyl
    818 —CH2 pyridin-3,5-diyl —O— 2-MeS-phenyl
    819 —CH2 pyridin-3,5-diyl —O— 3-MeS-phenyl
    820 —CH2 pyridin-3,5-diyl —O— 4-MeS-phenyl
    821 —CH2 pyridin-3,5-diyl —O— 2-F3C-phenyl
    822 —CH2 pyridin-3,5-diyl —O— 3-F3C-phenyl
    823 —CH2 pyridin-3,5-diyl —O— 4-F3C-phenyl
    824 —CH2 pyridin-3,5-diyl —O— 2,3-diF-phenyl
    825 —CH2 pyridin-3,5-diyl —O— 2,4-diF-phenyl
    826 —CH2 pyridin-3,5-diyl —O— 2,5-diF-phenyl
    827 —CH2 pyridin-3,5-diyl —O— 2,6-diF-phenyl
    828 —CH2 pyridin-3,5-diyl —O— 3,4-diF-phenyl
    829 —CH2 pyridin-3,5-diyl —O— 3,5-diF-phenyl
    830 —CH2 pyridin-3,5-diyl —O— 2,3-diCl-phenyl
    831 —CH2 pyridin-3,5-diyl —O— 2,4-diCl-phenyl
    832 —CH2 pyridin-3,5-diyl —O— 2,5-diCl-phenyl
    833 —CH2 pyridin-3,5-diyl —O— 2,6-diCl-phenyl
    834 —CH2 pyridin-3,5-diyl —O— 3,4-diCl-phenyl
    835 —CH2 pyridin-3,5-diyl —O— 3,5-diCl-phenyl
    836 —CH2 pyridin-3,5-diyl —O— 2-Cl-3-F-phenyl
    837 —CH2 pyridin-3,5-diyl —O— 2-Cl-4-F-phenyl
    838 —CH2 pyridin-3,5-diyl —O— 2-Cl-5-F-phenyl
    839 —CH2 pyridin-3,5-diyl —O— 3-Cl-4-F-phenyl
    840 —CH2 pyridin-3,5-diyl —O— 3-Cl-5-F-phenyl
    841 —CH2 pyridin-3,5-diyl —O— 4-Cl-2-F-phenyl
    842 —CH2 pyridin-3,5-diyl —O— 4-Cl-3-F-phenyl
    843 —CH2 pyridin-3,5-diyl —O— 2,3-diMeO-phenyl
    844 —CH2 pyridin-3,5-diyl —O— 2,4-diMeO-phenyl
    845 —CH2 pyridin-3,5-diyl —O— 2,5-diMeO-phenyl
    846 —CH2 pyridin-3,5-diyl —O— 2,6-diMeO-phenyl
    847 —CH2 pyridin-3,5-diyl —O— 3,4-diMeO-phenyl
    848 —CH2 pyridin-3,5-diyl —O— 3,5-diMeO-phenyl
    849 —CH2 pyridin-3,5-diyl —O— cyclopropyl
    850 —CH2 pyridin-3,5-diyl —O— cyclobutyl
    851 —CH2 pyridin-3,5-diyl —O— cyclopentyl
    852 —CH2 pyridin-3,5-diyl —O— cyclohexyl
    853 —CH2 pyridin-3,5-diyl —O— 2-furanyl
    854 —CH2 pyridin-3,5-diyl —O— 2-thienyl
    855 —CH2 pyridin-3,5-diyl CH2CH2 2-imidazolyl
    856 —CH2 pyridin-3,5-diyl —O— 2-pyridyl
    857 —CH2 pyridin-3,5-diyl —O— 3-pyridyl
    858 —CH2 pyridin-3,5-diyl —O— 4-pyridyl
    859 —CH2 pyridin-3,5-diyl CH2CH2 N-morpholinyl
    860 —CH2 pyridin-3,5-diyl CH2CH2 N-piperidinyl
    861 —CH2 pyridin-3,5-diyl —O— 3-Me-2-pyridyl
    862 —CH2 pyridin-3,5-diyl —O— 4-Me-2-pyridyl
    863 —CH2 pyridin-3,5-diyl CH2CH2 1-indolyl
    864 —CH2 pyridin-3,5-diyl —O— 2-benzothienyl
    865 —CH2 pyridin-3,5-diyl —O— 2-benzofuranyl
    866 —CH2 pyridin-3,5-diyl CH2CH2 1-benzimidazole
    867 —CH2 pyridin-3,5-diyl —O— 2-naphthyl
    868 —CH2 pyridin-2,6-diyl —O— phenyl
    869 —CH2 pyridin-2,6-diyl —O— 3,3-diphenylmethyl
    870 —CH2 pyridin-2,6-diyl —O— 2-F-phenyl
    871 —CH2 pyridin-2,6-diyl —O— 3-F-phenyl
    872 —CH2 pyridin-2,6-diyl —O— 4-F-phenyl
    873 —CH2 pyridin-2,6-diyl —O— 2-Cl-phenyl
    874 —CH2 pyridin-2,6-diyl —O— 3-Cl-phenyl
    875 —CH2 pyridin-2,6-diyl —O— 4-Cl-phenyl
    876 —CH2 pyridin-2,6-diyl —O— 2-Me-phenyl
    877 —CH2 pyridin-2,6-diyl —O— 3-Me-phenyl
    878 —CH2 pyridin-2,6-diyl —O— 4-Me-phenyl
    879 —CH2 pyridin-2,6-diyl —O— 2-MeO-phenyl
    880 —CH2 pyridin-2,6-diyl —O— 3-MeO-phenyl
    881 —CH2 pyridin-2,6-diyl —O— 4-MeO-phenyl
    882 —CH2 pyridin-2,6-diyl —O— 2-MeS-phenyl
    883 —CH2 pyridin-2,6-diyl —O— 3-MeS-phenyl
    884 —CH2 pyridin-2,6-diyl —O— 4-MeS-phenyl
    885 —CH2 pyridin-2,6-diyl —O— 2-F3C-phenyl
    886 —CH2 pyridin-2,6-diyl —O— 3-F3C-phenyl
    887 —CH2 pyridin-2,6-diyl —O— 4-F3C-phenyl
    888 —CH2 pyridin-2,6-diyl —O— 2,3-diF-phenyl
    889 —CH2 pyridin-2,6-diyl —O— 2,4-diF-phenyl
    890 —CH2 pyridin-2,6-diyl —O— 2,5-diF-phenyl
    891 —CH2 pyridin-2,6-diyl —O— 2,6-diF-phenyl
    892 —CH2 pyridin-2,6-diyl —O— 3,4-diF-phenyl
    893 —CH2 pyridin-2,6-diyl —O— 3,5-diF-phenyl
    894 —CH2 pyridin-2,6-diyl —O— 2,3-diCl-phenyl
    895 —CH2 pyridin-2,6-diyl —O— 2,4-diCl-phenyl
    896 —CH2 pyridin-2,6-diyl —O— 2,5-diCl-phenyl
    897 —CH2 pyridin-2,6-diyl —O— 2,6-diCl-phenyl
    898 —CH2 pyridin-2,6-diyl —O— 3,4-diCl-phenyl
    899 —CH2 pyridin-2,6-diyl —O— 3,5-diCl-phenyl
    900 —CH2 pyridin-2,6-diyl —O— 2-Cl-3-F-phenyl
    901 —CH2 pyridin-2,6-diyl —O— 2-Cl-4-F-phenyl
    902 —CH2 pyridin-2,6-diyl —O— 2-Cl-5-F-phenyl
    903 —CH2 pyridin-2,6-diyl —O— 3-Cl-4-F-phenyl
    904 —CH2 pyridin-2,6-diyl —O— 3-Cl-5-F-phenyl
    905 —CH2 pyridin-2,6-diyl —O— 4-Cl-2-F-phenyl
    906 —CH2 pyridin-2,6-diyl —O— 4-Cl-3-F-phenyl
    907 —CH2 pyridin-2,6-diyl —O— 2,3-diMeO-phenyl
    908 —CH2 pyridin-2,6-diyl —O— 2,4-diMeO-phenyl
    909 —CH2 pyridin-2,6-diyl —O— 2,5-diMeO-phenyl
    910 —CH2 pyridin-2,6-diyl —O— 2,6-diMeO-phenyl
    911 —CH2 pyridin-2,6-diyl —O— 3,4-diMeO-phenyl
    912 —CH2 pyridin-2,6-diyl —O— 3,5-diMeO-phenyl
    913 —CH2 pyridin-2,6-diyl —O— cyclopropyl
    914 —CH2 pyridin-2,6-diyl —O— cyclobutyl
    915 —CH2 pyridin-2,6-diyl —O— cyclopentyl
    916 —CH2 pyridin-2,6-diyl —O— cyclohexyl
    917 —CH2 pyridin-2,6-diyl —O— 2-furanyl
    918 —CH2 pyridin-2,6-diyl —O— 2-thienyl
    919 —CH2 pyridin-2,6-diyl CH2CH2 2-imidazolyl
    920 —CH2 pyridin-2,6-diyl —O— 2-pyridyl
    921 —CH2 pyridin-2,6-diyl —O— 3-pyridyl
    922 —CH2 pyridin-2,6-diyl —O— 4-pyridyl
    923 —CH2 pyridin-2,6-diyl CH2CH2 N-morpholinyl
    924 —CH2 pyridin-2,6-diyl CH2CH2 N-piperidinyl
    925 —CH2 pyridin-2,6-diyl —O— 3-Me-2-pyridyl
    926 —CH2 pyridin-2,6-diyl —O— 4-Me-2-pyridyl
    927 —CH2 pyridin-2,6-diyl CH2CH2 1-indolyl
    928 —CH2 pyridin-2,6-diyl —O— 2-benzothienyl
    929 —CH2 pyridin-2,6-diyl —O— 2-benzofuranyl
    930 —CH2 pyridin-2,6-diyl CH2CH2 1-benzimidazole
    931 —CH2 pyridin-2,6-diyl —O— 2-naphthyl
    932 —CH2 pyridin-2,4-diyl —O— phenyl
    933 —CH2 pyridin-2,4-diyl —O— 3,3-diphenylmethyl
    934 —CH2 pyridin-2,4-diyl —O— 2-F-phenyl
    935 —CH2 pyridin-2,4-diyl —O— 3-F-phenyl
    936 —CH2 pyridin-2,4-diyl —O— 4-F-phenyl
    937 —CH2 pyridin-2,4-diyl —O— 2-Cl-phenyl
    938 —CH2 pyridin-2,4-diyl —O— 3-Cl-phenyl
    939 —CH2 pyridin-2,4-diyl —O— 4-Cl-phenyl
    940 —CH2 pyridin-2,4-diyl —O— 2-Me-phenyl
    941 —CH2 pyridin-2,4-diyl —O— 3-Me-phenyl
    942 —CH2 pyridin-2,4-diyl —O— 4-Me-phenyl
    943 —CH2 pyridin-2,4-diyl —O— 2-MeO-phenyl
    944 —CH2 pyridin-2,4-diyl —O— 3-MeO-phenyl
    945 —CH2 pyridin-2,4-diyl —O— 4-MeO-phenyl
    946 —CH2 pyridin-2,4-diyl —O— 2-MeS-phenyl
    947 —CH2 pyridin-2,4-diyl —O— 3-MeS-phenyl
    948 —CH2 pyridin-2,4-diyl —O— 4-MeS-phenyl
    949 —CH2 pyridin-2,4-diyl —O— 2-F3C-phenyl
    950 —CH2 pyridin-2,4-diyl —O— 3-F3C-phenyl
    951 —CH2 pyridin-2,4-diyl —O— 4-F3C-phenyl
    952 —CH2 pyridin-2,4-diyl —O— 2,3-diF-phenyl
    953 —CH2 pyridin-2,4-diyl —O— 2,4-diF-phenyl
    954 —CH2 pyridin-2,4-diyl —O— 2,5-diF-phenyl
    955 —CH2 pyridin-2,4-diyl —O— 2,6-diF-phenyl
    956 —CH2 pyridin-2,4-diyl —O— 3,4-diF-phenyl
    957 —CH2 pyridin-2,4-diyl —O— 3,5-diF-phenyl
    958 —CH2 pyridin-2,4-diyl —O— 2,3-diCl-phenyl
    959 —CH2 pyridin-2,4-diyl —O— 2,4-diCl-phenyl
    960 —CH2 pyridin-2,4-diyl —O— 2,5-diCl-phenyl
    961 —CH2 pyridin-2,4-diyl —O— 2,6-diCl-phenyl
    962 —CH2 pyridin-2,4-diyl —O— 3,4-diCl-phenyl
    963 —CH2 pyridin-2,4-diyl —O— 3,5-diCl-phenyl
    964 —CH2 pyridin-2,4-diyl —O— 2-Cl-3-F-phenyl
    965 —CH2 pyridin-2,4-diyl —O— 2-Cl-4-F-phenyl
    966 —CH2 pyridin-2,4-diyl —O— 2-Cl-5-F-phenyl
    967 —CH2 pyridin-2,4-diyl —O— 3-Cl-4-F-phenyl
    968 —CH2 pyridin-2,4-diyl —O— 3-Cl-5-F-phenyl
    969 —CH2 pyridin-2,4-diyl —O— 4-Cl-2-F-phenyl
    970 —CH2 pyridin-2,4-diyl —O— 4-Cl-3-F-phenyl
    971 —CH2 pyridin-2,4-diyl —O— 2,3-diMeO-phenyl
    972 —CH2 pyridin-2,4-diyl —O— 2,4-diMeO-phenyl
    973 —CH2 pyridin-2,4-diyl —O— 2,5-diMeO-phenyl
    974 —CH2 pyridin-2,4-diyl —O— 2,6-diMeO-phenyl
    975 —CH2 pyridin-2,4-diyl —O— 3,4-diMeO-phenyl
    976 —CH2 pyridin-2,4-diyl —O— 3,5-diMeO-phenyl
    977 —CH2 pyridin-2,4-diyl —O— cyclopropyl
    978 —CH2 pyridin-2,4-diyl —O— cyclobutyl
    979 —CH2 pyridin-2,4-diyl —O— cyclopentyl
    980 —CH2 pyridin-2,4-diyl —O— cyclohexyl
    981 —CH2 pyridin-2,4-diyl —O— 2-furanyl
    982 —CH2 pyridin-2,4-diyl —O— 2-thienyl
    983 —CH2 pyridin-2,4-diyl —O— 2-imidazolyl
    984 —CH2 pyridin-2,4-diyl —O— 2-pyridyl
    985 —CH2 pyridin-2,4-diyl —O— 3-pyridyl
    986 —CH2 pyridin-2,4-diyl —O— 4-pyridyl
    987 —CH2 pyridin-2,4-diyl CH2CH2 N-morpholinyl
    988 —CH2 pyridin-2,4-diyl CH2CH2 N-piperidinyl
    989 —CH2 pyridin-2,4-diyl —O— 3-Me-2-pyridyl
    990 —CH2 pyridin-2,4-diyl —O— 4-Me-2-pyridyl
    991 —CH2 pyridin-2,4-diyl CH2CH2 1-indolyl
    992 —CH2 pyridin-2,4-diyl —O— 2-benzothienyl
    993 —CH2 pyridin-2,4-diyl —O— 2-benzofuranyl
    994 —CH2 pyridin-2,4-diyl CH2CH2 1-benzimidazole
    995 —CH2 pyridin-2,4-diyl —O— 2-naphthyl
    996 —CH2 pyridin-4,2-diyl —O— phenyl
    997 —CH2 pyridin-4,2-diyl —O— 3,3-diphenylmethyl
    998 —CH2 pyridin-4,2-diyl —O— 2-F-phenyl
    999 —CH2 pyridin-4,2-diyl —O— 3-F-phenyl
    1000  —CH2 pyridin-4,2-diyl —O— 4-F-phenyl
    1001  —CH2 pyridin-4,2-diyl —O— 2-Cl-phenyl
    1002  —CH2 pyridin-4,2-diyl —O— 3-Cl-phenyl
    1003  —CH2 pyridin-4,2-diyl —O— 4-Cl-phenyl
    1004  —CH2 pyridin-4,2-diyl —O— 2-Me-phenyl
    1005  —CH2 pyridin-4,2-diyl —O— 3-Me-phenyl
    1006  —CH2 pyridin-4,2-diyl —O— 4-Me-phenyl
    1007  —CH2 pyridin-4,2-diyl —O— 2-MeO-phenyl
    1008  —CH2 pyridin-4,2-diyl —O— 3-MeO-phenyl
    1009  —CH2 pyridin-4,2-diyl —O— 4-MeO-phenyl
    1010  —CH2 pyridin-4,2-diyl —O— 2-MeS-phenyl
    1011  —CH2 pyridin-4,2-diyl —O— 3-MeS-phenyl
    1012  —CH2 pyridin-4,2-diyl —O— 4-MeS-phenyl
    1013  —CH2 pyridin-4,2-diyl —O— 2-F3C-phenyl